The hypoglycemic side of hypothyroidism

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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 modifi 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 classifi 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 effi 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 confl 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 defi 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 insuffi 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 fl 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 insignifi cant aspect of hypothyroidism, which
has a signifi 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 signifi 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 nonspecifi 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.
REFERENCES
1. Heller SR. Hypoglycemia and diabetes. In: Pickup JC, Williams G,
editors. Textbook of Diabetes. Malden: Blackwell; 2003. p. 33.1-33.19.
2. Kalra S, Deepak MC, Narang P, Singh V, Uvaraj MG, Agrawal N.
Usage pattern, glycemic improvement, hypoglycemia, and body
mass index changes with sulfonylureas in real-life clinical practice:
Results from OBSTACLE Hypoglycemia Study. Diabetes Technol
Ther 2013;15:129-35.
3. Unnikrishnan AG, Menon UV. Thyroid disorders in India: An
epidemiological perspective. Indian J Endocrinol Metab 2011;15:S78-81.
4. Kalra S, Kalra B, Chatley G. Prevalence of hypothyroidism in
pediatric type 1 diabetes mellitus in Haryana, Northern India.
Thyroid Res Pract 2012;9:12-4.
5. Demitrost L, Ranabir S. Thyroid dysfunction in type 2 diabetes
mellitus: A retrospective study. Indian J Endocrinol Metab
2012;16:S334-5.
6. John HJ. Association of hyperthyroidism with diabetes. Ann Surg
1928;87:37-47.
7. Kalra S, Dhamija P, Unnikrishnan AG. Metformin and the thyroid:
An unexplored therapeutic option. Thyroid Res Pract 2012;9:75-7.
8. Janney NW, Isaacson VI. I. The blood sugar in thyroid and other
endocrine diseases: The significance of hypoglycemia and the
delayed blood sugar curve. Arch Intern Med 1918;22:160.
9. Simpson VE. Thyrotoxicosis and associated vagotonic and
sympathicotonic syndromes. Am J Surg 1927;3:249-54.
10. Shah JH, Motto GS, Papagiannes E, Williams GA. Insulin
Metabolism in hypothyroidism. Diabetes 1975;24:922-5.
11. Rohdenburg GL. Thyroid diabetes. Endocrinology 1920;4:63.
12. Nobel Lecture. Available from: http://www.nobelprize.org/
nobel_prizes/medicine/laureates/1947/houssay-lecture.html
[Last accessed on 2013 May 30].
13. Mc De rmott MT. Overview of the clinical manifestations of
hypothyroidism. In: Braverman LE, Cooper DS, editors. Werner
and Ingbar’s The Thyroid. A Fundamental and Clinical Text. 10th ed.
New Delhi, Philadelphia: Lippincott. William and Wilkins; 2013.
14. Samaan NA. Hypoglycemia secondary to endocrine deficiencies.
Endocrinol Metab Clin North Am 1989;18:145-54.
15. Saleh M, Grunberger G. Hypoglycemia: An excuse for poor glycemic
control? Clin Diabetes 2001;19:161-7.
16. Brenta G. Why can insulin resistance be a natural consequence of
thyroid dysfunction? J Thyroid Res 2011;1:2011.
17. Kurtoglu S, Tutuş A, Aydin K, Genç E, Çaksen H. Persistent neonatal
hypoglycemia: An unusual finding of congenital hypothyroidism.
J Pediatr Endocrinol Metab 1998;11:277-9.
18. Shibutani Y, Yokota T. A case of acetohexamide-induced
hypoglycemia: The influence of hypothyroidism on the metabolism
of acetohexamide. Nihon Naibunpi Gakkai Zasshi 1991;67:42-9.
19. Wu P. Thyroid disease and diabetes. Clin Diabetes 2000;18:38-9.
20. Ridgway EC, McCammon JA, Benotti J, Maloof F. Acute metabolic
responses in myxedema to large doses of intravenous L-thyroxine.
Ann Intern Med 1972;77:549-55.
21. Katz HP, Youlton R, Kaplan SL, Grumbach MM. Growth and
growth hormone. 3. Growth hormone release in children with
primary hypothyroidism and thyrotoxicosis J Clin Endocrinol Metab
1969;29:346-51.
22. Kamilaris TC, DeBold CR, Pavlou SN, Island DP, Hoursanidis A,
Orth DN. Effect of altered thyroid hormone levels on
hypothalamic-pituitary-adrenal function J Clin Endocrinol Metab
1987;65:994-9.
23. McCulloch AJ, Johnston DG, Baylis PH, Kendall-Taylor P,
Clark F, Young ET, et al. Evidence that thyroid hormones regulate
gluconeogenesis from glycerol in man. Clin Endocrinol (Oxf)
1983;19:67-76.
24. McDaniel HG, Pittman CS, Oh SJ, DiMauro S. Carbohydrate
metabolism in hypothyroid myopathy. Metabolism 1977;26:867-73.
25. Clausen N, Lins PE, Adamson U, Hamberger B, Efendić S.
Counterregulation of insulin-induced hypoglycaemia in primary
hypothyroidism. Acta Endocrinol (Copenh) 1986;111:516-21.
26. Müller MJ, Seitz HJ. Interrelation between thyroid state and the
effect of glucagon on gluconeogenesis in perfused rat livers. Biochem
Pharmacol 1987;36:1623-7.
27. Holdsworth CD, Besser GM. Influence of gastric emptying-rate
and of insulin response on oral glucose tolerance in thyroid disease.
Lancet 1968;2:700-2.
28. Singh BM, Goswami B, Mallika V. Association between insulin
resistance and hypothyroidism in females attending a tertiary care
hospital. Indian J Clin Biochem 2010;25:141-5.
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, Confl ict of Interest: None declared.
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