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Indian Journal of Endocrinology and Metabolism / Jan-Feb 2014 / Vol 18 | Issue 1 1
Hypoglycemia is a not so infrequent condition encountered
in endocrine practice. Considered an inevitable
(though modi able) part of diabetes therapy, hypoglycemia
occurs fairly often, in both type 1 and type 2 diabetes, in
patients on oral hypoglycemic agents and insulin, and in
indoor as well as outdoor settings.[1] As the prevalence
of diabetes rises, and as we try to control glycemia
more aggressively, using the multiple permutations and
combinations of antidiabetic drugs available to us, the
incidence of hypoglycemia is certain to rise. Apart from
this, hypoglycemia is sometimes spontaneous, and may
occur without relation to antidiabetic therapy.
Hypoglycemia is basically a mismatch between
insulin (whether exogenous or endogenous) and glycemic
levels (whether produced by meals or parenteral nutrition).
The excessive insulin levels may be due to excessive dosage,
increased bioavailability, or enhanced insulin sensitivity.
The inappropriate increase in insulin levels leads to a fall
in blood glucose levels, which in turn stimulates a series of
physiological protective mechanisms. These include a release
of glucagon, adrenaline, cortisol, and growth hormone;
among others.[1] These physiological responses are linked with
symptoms, which can be classi ed as adrenergic or autonomic,
neuroglycopenic, and general (usually glucagon-induced).
Hypoglycemia prevention now occupies center stage in
diabetes praxis, as focus moves from a purely ef cacy
oriented approach to one which aims for safety and
tolerability, along with glycemic control. This shift has
occurred in parallel with our understanding of the multiple
deleterious effects of hypoglycemia on various organ
systems; including the heart, brain, and retina.[2]
Hypothyroidism is one of the most common
endocrinopathies worldwide, and its incidence is increasing
rapidly.[3] It is frequently found to coexist with both type 1
and type 2 diabetes mellitus.[4,5] Cross-talk between thyroid
and diabetes has been the topic of many reviews, which
discuss the potential of hyperthyroidism to exacerbate
diabetes,[6] and of antidiabetic therapy (metformin)
to improve thyroid function.[7] The potential role of
hypothyroidism in precipitating hypoglycemia has not
been highlighted adequately in current literature. This
brief communication aims to discuss the link between
hypothyroidism and hypoglycemia, and suggest simple
caveats for clinical practice.
EARLY LITERATURE
Interest in the hypoglycemic effect of hypothyroidism
began a century ago, even before insulin was discovered.[8]
Hypothyroidism was, by then, a well-known and well-studied
entity, and had been differentiated from hypopituitarism.
The hypoglycemia of hypothyroidism, dyspituitarism,
and Addison’s disease was known to be common
knowledge.[9] Later, literature clearly highlights the importance
of hypothyroidism as a precipitating factor for hypoglycemia,
while reporting prolonged hypoglycemia due to exogenously
administered insulin in hypothyroid patients.[10]
The correlation between diabetes and hyperthyroidism had
also been reported before the advent of the insulin era.[11] In
fact, in his 1947 Nobel lecture, Nobel laureate BA Houssay
clearly mentions thyroid as one of the ‘blood sugar raising’
glands (aneterohypophysis, adrenals, thyroid, etc.)[12]
RECENT LITERATURE
Recent literature, however, is con icting and confusing.
Some diabetology textbooks choose not to mention
Editorial
The hypoglycemic side of hypothyroidism
Sanjay Kalra, Ambika Gopalakrishnan Unnikrishnan1, Rakesh Sahay2
Departments of Endocrinology, Bharti Hospital and BRIDE, Karnal, Haryana, 1Chellaram Institute of Diabetes, Pune, Maharashtra,
2Osmania Medical College, Hyderabad, Andhra Pradesh, India
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DOI:
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Corresponding Author: Dr. Sanjay Kalra, Bharti Hospital and BRIDE, Karnal, Haryana, E-mail: brideknl@gmail.com
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Kalra, et al.: Hypothyroidism and hypoglycemia
Indian Journal of Endocrinology and Metabolism / Jan-Feb 2014 / Vol 18 | Issue 1
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hypothyroidism as a possible factor in the pathogenesis of
hypoglycemia, though they do describe Addison’s disease
and panhypopituitarism.[1] Major thyroidology textbooks do
not mention susceptibility to hypoglycemia as a complication
of hypothyroidism.[13] Other modern reviewers, on the
other hand, clearly emphasize hypothyroidism as one of
the endocrine de ciencies responsible for hypoglycemia.[14]
Yet others refute this concept, proposing the theory that
if hypothyroidism is accompanied by hypoglycemia, it is
in fact a manifestation of panhypopituitarism, rather than
primary hypothyroid disease.[15] Yet others tend to trivialize
the issue (‘although seldom happening, hypothyroid patients
can experience hypoglycemia’).[16]
Yet, case reports have been published which describe the
correlation between hypothyroidism and hypoglycemia,
both in infants[17] and in adults.[18] Robust evidence is also
available which implicates uncontrolled hyperthyroidism
as a cause of poor glycemic control.[19]
Is there a physiologic basis to connect hypothyroidism
and hypoglycemia? And if we go a step further, can
hypothyroidism be postulated as a precipitating factor for
hypoglycemia unawareness?
PATHOPHYSIOLOGIC CORRELATION:
HYPOTHYROIDISM AND HYPOGLYCEMIA
Hypothyroidism is linked with various hormonal
biochemical and nervous system abnormalities, which
may contribute to hypoglycemia.
The condition is linked with low growth hormone and
cortisol responses to insulin induced hypoglycemia, and
this prevents adequate counter regulatory protection.[20,21] It
must be noted that in some cases, pituitary dysfunction may
be a consequence of primary hypothyroidism, rather than a
cause of thyroid dysfunction. For example, hypothyroidism
reduces basal and stimulated growth hormone levels, by
acting on both the hypothalamus and pituitary.[21] As it
is linked with suboptimal growth hormone response,
the recovery from hypoglycemia may be prolonged in
hypothyroidism.
Hypothyroid patients have relative adrenal insuf ciency,
even if they are not associated with primary adrenal failure.
There is a blunted hypothalamo-pituitary-adrenal response
to hypoglycemia in hypothyroid persons.[22] The reduced
cortisol responses to insulin-induced hypoglycemia that
are noted in hypothyroidism also worsen hypoglycemia.
The role of gluconeogenesis is reduced in hypothyroidism,
both in skeletal muscle and in adipose tissue.[23]
Glycogenolysis is also impaired in hypothyroidism.[24] These
biochemical defects lead to a delayed recovery from
hypoglycemia.
Other abnormalities in hypothyroidism include a
reduction in glucagon secretion,[25] reduced effect of
glucagon on hepatocytes,[26] and slowing of insulin
clearance.[10] Contributory factors also include the effect
of hypothyroidism on the gastro intestinal system. It slows
gastric emptying[27] and decreases intestinal absorption of
glucose as well as portal venous ow.
Modern researchers, on the other hand, have reported
the link between subclinical and overt hypothyroidism on
one hand, and insulin resistance on the other.[28] Reviewers
explain this paradox by contrasting the insulin agonist actions
of thyroid hormones, evident in peripheral tissues, with
insulin antagonist activity in the liver.[16] The hepatic effects
of thyroxin are mediated directly, as well as through the
hypothalamus. Variable effects at peripheral and hepatic levels
may explain discordant results obtained by different workers.
THERAPEUTIC IMPLICATION
The wisdom collated by the pioneers of endocrinology
seems to have been lost in modern textbooks. This
omission deprives the student of endocrinology of an
important clinical practice pearl, viz.: The hypoglycemic
side of hypothyroidism. This editorial has tried to highlight
a supposedly insigni cant aspect of hypothyroidism, which
has a signi cant impact on contemporary diabetology
practice. Perhaps the reason for this lack of attention is a
lack of clarity regarding the difference between spontaneous
hypoglycemia (as seen in panhypopituitarism) and the
increased predisposition to hypoglycemia encountered in
persons on treatment for diabetes.
The glucoregulatory effects of thyroid hormones carry
great clinical signi cance. Persons with diabetes who
report with a sudden increase in frequency or severity of
hypoglycemic episodes, not explained by changes in diet,
physical activity, or dosage of glucose-lowering drugs, must
be evaluated for hypothyroidism.
The symptoms of hypoglycemia may be nonspeci c, and
may represent subtle neuroglycopenia. A high index of
suspicion must be kept in hypothyroid patients on diabetes
treatment, as the symptoms of counter regulatory hormone
release may be blunted, and there may be an underlying
neurocognitive defect in grossly hypothyroid persons.
The clinical implications of the hypoglycemia-prone features
of hypothyroidism should be taken into account while
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Kalra, et al.: Hypothyroidism and hypoglycemia
Indian Journal of Endocrinology and Metabolism / Jan-Feb 2014 / Vol 18 | Issue 1 3
planning antidiabetic therapy. Person with uncontrolled
hypothyroidism should be given relatively lower doses of
insulin and insulin secretagogues (sulfonylureas). Safer
insulin analogues which are linked with a lower incidence
of hypoglycemia should be preferred.
In patients on treatment for both thyroid disorders and
diabetes, thyroid status should be kept in mind while titrating
antidiabetic therapy. Those with an improving thyroid
status, or falling serum thyroid stimulating hormone (TSH),
may require an increase in dosage of antidiabetic medicines.
Similarly, those with worsening hypothyroidism will need a
reduction in dosage. This down titration will be needed in
patients of Graves’ disease who respond rapidly to therapy.
The TSH lowering or potential thyroprotective effect of
metformin[7] should be considered while assessing thyroid
function reports. Above all, one must follow a panglandular
approach while managing any endocrine illness, and not
neglect the mature wisdom of clinical endocrinology.
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Cite this article as: Kalra S, Unnikrishnan AG, Sahay R. The hypoglycemic
side of hypothyroidism. Indian J Endocr Metab 2014;18:1-3.
Source of Support: Nil, Con ict of Interest: None declared.
[Downloaded free from http://www.ijem.in on Wednesday, September 28, 2016, IP: 77.253.230.104]
... The most common causes of hypoglycaemia in diabetic patients are: overdosing of oral hypoglycaemic agents or insulin with respect to meal and physical activity, renal or hepatic impairment [3]. In hypothyroidism gastrointestinal absorption of glucose and its utilization in the peripheral tissues is slowed [4][5][6]. Hepatic glucose output is decreased and insulin half-life is prolonged [4][5][6]. Doses of exogenous insulin may have to be decreased to avoid hypoglycaemia [5,6]. ...
... In hypothyroidism gastrointestinal absorption of glucose and its utilization in the peripheral tissues is slowed [4][5][6]. Hepatic glucose output is decreased and insulin half-life is prolonged [4][5][6]. Doses of exogenous insulin may have to be decreased to avoid hypoglycaemia [5,6]. However, after treatment with levothyroxine when thyroid function is normalized blood glucose levels may again increase to pre-treatment levels [4][5][6]. ...
... Hepatic glucose output is decreased and insulin half-life is prolonged [4][5][6]. Doses of exogenous insulin may have to be decreased to avoid hypoglycaemia [5,6]. However, after treatment with levothyroxine when thyroid function is normalized blood glucose levels may again increase to pre-treatment levels [4][5][6]. ...
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... Importantly, hypothyroidism, both overt and subclinical disease, was also associated with a deterioration of glucose metabolism and elevated whole-body IR; moreover, it appeared to be subject to an increased risk of hypoglycemia as a consequence of the mismatch between insulin and glycemic levels [115,116]. Furthermore, insulin-stimulated glucose transport was reported to decrease in patients with hypothyroidism due to disrupted translocation of GLUT4 on the plasma membrane [117]. On the other hand, IR was correlated with a higher prevalence and larger size of thyroid nodules and increased thyroid volume [118,119]. ...
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Evidence for a relationship between T4 and T3 and glucose metabolism appeared over 100 years ago when the influence of thyroid hormone excess in the deterioration of glucose metabolism was first noticed. Since then, it has been known that hyperthyroidism is associated with insulin resistance. More recently, hypothyroidism has also been linked to decreased insulin sensitivity. The explanation to this apparent paradox may lie in the differential effects of thyroid hormones at the liver and peripheral tissues level. The purpose of this paper is to explore the effects of thyroid hormones in glucose metabolism and analyze the mechanisms whereby alterations of thyroid hormones lead to insulin resistance.
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Objectives: This paper describes the prevalence of hypothyroidism, in young children and adolescents, aged less than 18 years, with type 1 diabetes mellitus, in northern India. Materials and Methods: Seventy patients (23 female, 47 male) were screened for hypothyroidism, using serum TSH, as part of a detailed assessment of the clinical profile of children and adolescents with type 1 diabetes in an endocrine centre located in Haryana, northern India. Results: Seven girls were found to have hypothyroidism of varying degree, and two boys had subclinical hypothyroidism. Conclusion: Thus, hypothyroidism is found to be a frequent association with type 1 diabetes mellitus in northern India.
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We have previously reported that glucose production assessed using radioiso-topic methods is 50% increased in hyperthyroidism but 30% decreased in hypothyroidism. These studies, however, do not distinguish between glycogenolysis and gluconeogenesis. In fasting man more than 80% of circulating glycerol is cleared by the liver and enters the gluconeogenic pathway. We have therefore measured glycerol clearance following bolus intravenous glycerol administration as an indirect assessment of gluconeogenic capacity. Hyperthyroid and hypothyroid subjects were compared with separate matched controls after an overnight fast. In hyperthyroid subjects blood glucose and blood glycerol were increased but lactate, pyruvate, and alanine concentrations were normal. Glycerol clearance was increased in hyperthyroidism and followed a double exponential decay with a shortened second component half-time. Endogenous glycerol production was increased three-fold. In hypothyroidism fasting circulating levels of glucose, lactate, pyruvate, alanine, and glycerol were normal but glycerol clearance was diminished. Both first and second component half-times were prolonged in hypothyroidism and endogenous glycerol production was decreased by 50%. Thus in hyperthyroidism glycerol clearance is greatly enhanced whilst in hypothyroidism glycerol clearance is diminished. The magnitude of the changes suggests that alterations in gluconeogenesis are probably the major factors concerned in the reported increase and decrease in glucose production in hyperthyroidism and hypothyroidism respectively.