Letters to the Editor

et al. Adiposity and hyperinsulinemia in Indians are present at birth. Access this article online
J Clin Endocrinol Metab 2002;87:5575‑80.
Quick Response Code:
10. Agrawal M, Kern PA, Nikolajczyk BS. The immune system in obesity:
Website:
Developing paradigms amidst inconvenient truths. Curr Diab Rep www.ijem.in
2017;17:87.

DOI:
10.4103/ijem.IJEM_67_18

This is an open access journal, and articles are distributed under the terms of the Creative
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remix, tweak, and build upon the work non-commercially, as long as appropriate credit
is given and the new creations are licensed under the identical terms.
How to cite this article: Prakash SS. Models that explain the cause of
obesity. Indian J Endocr Metab 2018;22:569-70.
© 2018 Indian Journal of Endocrinology and Metabolism | Published by Wolters Kluwer - Medknow

Importance of Variables in Nonalcoholic Fatty Liver Disease

Patients
Sir, Address for correspondence:
We read the article entitled “Profile of liver enzymes in Dr. Vivek Kumar Garg,
Department of Biochemistry, Government Medical College and
nonalcoholic fatty liver disease in patients with impaired glucose Hospital, Chandigarh ‑ 160 030, India.
tolerance (IGT) and newly detected untreated type 2 diabetes[1]” E‑mail: garg.vivek85@gmail.com
with keen interest. The authors have performed an interesting
study and revealed a significant role of liver enzymes in IGT Reference
and new‑onset treatment‑naive type 2 diabetic mellitus patients. 1. Sanyal  D, Mukherjee  P, Raychaudhuri  M, Ghosh  S, Mukherjee  S,
They have provided all the information in the manuscript Chowdhury  S, et al. Profile of liver enzymes in non‑alcoholic fatty
liver disease in patients with impaired glucose tolerance and newly
except the table showing the significant correlation of alanine
detected untreated type  2 diabetes. Indian J Endocrinol Metab
aminotransferase (ALT) and gamma‑glutamyltransferase (GGT) 2015;19:597‑601.
with fasting insulin, waist circumferences, waist height ratio, body
mass index, waist hip ratio, high‑density lipoprotein cholesterol,
triglyceride, and fasting blood glucose. These variables are This is an open access journal, and articles are distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to
equally important as other variables. They also demonstrated that remix, tweak, and build upon the work non-commercially, as long as appropriate credit
homeostatic model assessment insulin resistance and quantitative is given and the new creations are licensed under the identical terms.
insulin-sensitivity check index are strongly associated with ALT
and GGT but did not provide any table showing this correlation. Access this article online
In conclusion, the authors should provide all the important Quick Response Code:
Website:
information which is related with the manuscript. www.ijem.in

Financial support and sponsorship

Nil. DOI:
10.4103/ijem.IJEM_120_18
Conflicts of interest
There are no conflicts of interest.

Vivek Kumar Garg1, Neelam Goel2 How to cite this article: Garg VK, Goel N. Importance of variables
in nonalcoholic fatty liver disease patients. Indian J Endocr Metab
Department of Biochemistry, Government Medical College and Hospital,
1
2018;22:570.
2
Department of Information Technology, University Institute of Engineering and
© 2018 Indian Journal of Endocrinology and Metabolism | Published by Wolters Kluwer - Medknow
Technology, Panjab University, Chandigarh, India

Strain, Diet, and Gender Influence the Role of miR155 in

Diabetes Mellitus
Sir, tissues studied is essential to decipher the role of miR155 in
An integrated view of genetic background, gender, and the diabetes mellitus.

570 Indian Journal of Endocrinology and Metabolism  ¦  Volume 22  ¦  Issue 4  ¦  July-August 2018
 Letters to the Editor
MicroRNAs (miRNAs) are increasingly being discovered to
mediate several physiological and pathological processes.
miRNAs are secreted in vesicles in exosomes and are thought
to have paracrine or endocrine effects by suppressing the
expression of genes in different tissues. One of the miRNAs,
namely miR155, has been extensively studied in immunological
and metabolic diseases. miR155 has been shown to be
expressed in immune cells and other tissues including adipose
tissue and are thought to be involved in several diseases
including diabetes mellitus.[1‑3] miR155 regulates a number
of genes involved in adipogenesis and those involved in
carbohydrate and lipid metabolism.[2] Adipocyte‑derived
miR155 has been demonstrated to take part in the polarization
of M1 macrophages and influence diet‑induced obesity.[4]
In this article, we analyze the role of miR155 in mediating
insulin resistance, nonalcoholic steatohepatitis, and diabetes
in studies done in mice. Two studies have analyzed the role
of miR155 in diet‑induced obesity and hepatic steatosis in
C57BL/6 strain.[5,6] Miller et al. found that miR155 knockout
mice in C57BL/6 background developed increased hepatic
steatosis in comparison to wild‑type mice when they were
fed high‑fat diet.[5] This study was done only in male mice.
Another study by Gaudet et al. reported that miR155 knockout
female mice in C57BL/6 background were protected from
high‑fat diet‑induced obesity but not male mice.[6] In addition,
they also showed that there was less increase in white adipose
tissue weight in both male and female mice fed high‑fat diet.
With respect to glucose metabolism, it was found that female
mice with miR155 knockout had improved responses. There
was no such improvement noticed in male mice with miR155
knockout in both these studies. It can be summarized from
these two studies that in C57BL/6 strain, knockout of miR155
in female mice is associated with protection from obesity and
dysfunctional glucose metabolism, a decrease in adipose tissue
weight in both male and female miR155 knockout mice, and
increased liver steatosis in male miR155 knockout mice. These
findings highlight the differential role of miR155 in different
gender and tissues analyzed in this particular strain. Similar
results have been reported in another recent study done in
this strain.[7]
In another recent study, Ying et  al. explored the miRNAs
secreted by adipose tissue macrophages and found that
miR155 expression was higher in exosomes from obese mice
in comparison to lean mice.[8] They further demonstrated that
administration of exosomes from obese mice to lean mice
made them insulin resistant by affecting the signaling in
muscle, liver, and adipose tissue. In contrast, exosomes from
lean mice were protective when administered to obese mice
and improved insulin resistance. The same authors studied the
effect of high‑fat diet in miR155 knockout animals (in C57BL/6
background) and found that insulin sensitivity was better
among these mice compared to control mice fed with
high‑fat diet. This is in stark contrast to another report
where the authors found that the deficiency of miR155 led to
hyperglycemia and insulin resistance compared to wild‑type
Indian Journal of Endocrinology and Metabolism  ¦  Volume 22  ¦  Issue 4  ¦  July-August 2018
Th1-biased (Ex. C57BL/6)
Strain
Th2-biased (Ex. FVB/N)
miR-155 in the
analyzed tissues
Diet
Chow diet
High-fat diet
Phenotypes – obesity,
fatty liver, adiposity,
Male glucose intolerance
Gender
Female
Figure 1: Factors affecting the levels of miR155 in serum and tissues and
their role in the causation of insulin resistance and diabetes mellitus can
be influenced by a concerted action of strain, diet, and gender. Dotted
lines represent the effects mediated through changes in miR155 levels
mice.[9] However, these mice were not fed with high‑fat diet.
These authors also studied the effects of overexpression of
miR155 on insulin resistance and found that global transgenic
overexpression of miR155 led to improvement in insulin
sensitivity and glucose tolerance. However, this study was
done in FVB/N strain which is different in immunological
responses as well as susceptibility to diet‑induced obesity
than C57BL/6 strain. They also found that overexpression of
miR155 led to improved insulin signaling in liver, muscle, and
adipose tissue, contrary to the findings of Ying et al.[8] These
findings highlight the importance of the influence of genetic
background in metabolic studies.
The comparative analysis of studies reporting on the role of
miR155 in metabolic diseases presented in this article suggests
the importance of considering the influence of background
strain, gender of mice, and the tissues analyzed in various
studies.[10] It is, therefore, important that the findings are
interpreted by considering these variables [Figure 1] which
may influence outcomes in these types of studies to have an
impact on translational medicine.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
V. Padmanaban, S. S. Prakash
Department of Biochemistry, Christian Medial College, Vellore, Tamil Nadu, India
Address for correspondence:
Dr. S. S. Prakash,
Department of Biochemistry, Christian Medical College,
Vellore ‑ 632 002, Tamil Nadu, India.
E‑mail: sspcmc@cmcvellore.ac.in
References
1. Klöting N, Berthold S, Kovacs P, Schön MR, Fasshauer M, Ruschke K,
et al. MicroRNA expression in human omental and subcutaneous
adipose tissue. PLoS One 2009;4:e4699.
2. Shantikumar S, Caporali A, Emanueli C. Role of microRNAs in diabetes
and its cardiovascular complications. Cardiovasc Res 2012;93:583‑93.
3. Assar ME, Angulo J, Rodríguez‑Mañas L. Diabetes and ageing‑induced
vascular inflammation. J Physiol 2016;594:2125‑46.
571
 Letters to the Editor
4. Zhang Y, Mei H, Chang X, Chen F, Zhu Y, Han X, et al. Adipocyte‑derived
microvesicles from obese mice induce M1 macrophage phenotype
through secreted miR‑155. J Mol Cell Biol 2016;8:505‑17.
5. Miller AM, Gilchrist DS, Nijjar J, Araldi E, Ramirez CM, Lavery CA,
et al. MiR‑155 has a protective role in the development of non‑alcoholic
hepatosteatosis in mice. PLoS One 2013;8:e72324.
6. Gaudet  AD, Fonken  LK, Gushchina  LV, Aubrecht  TG, Maurya  SK,
Periasamy M, et al. MiR‑155 deletion in female mice prevents
diet‑induced obesity. Sci Rep 2016;6:22862.
7. Velázquez KT, Enos  RT, Carson  MS, Cranford  TL, Bader  JE,
Sougiannis  AT, et al. MiR155 deficiency aggravates high‑fat
diet‑induced adipose tissue fibrosis in male mice. Physiol Rep 2017;5.
pii: e13412.
8. Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB,
et al. Adipose tissue macrophage‑derived exosomal miRNAs can modulate
in vivo and in vitro insulin sensitivity. Cell 2017;171:372‑84.e12.
9. Lin  X, Qin Y, Jia  J, Lin  T, Lin  X, Chen  L, et al. MiR‑155 enhances
insulin sensitivity by coordinated regulation of multiple genes in mice.
PLoS Genet 2016;12:e1006308.
10. Prakash SS. Immune class regulation as an integrated response of factors
related to host, stimulus and context. Scand J Immunol 2018;87:e12656.
Base Rate, Occam’s Razor, and Hypoglycemia
Sir,
Recently, we encountered a patient with recurrent hypoglycemia.
She was a middle‑aged Punjabi woman, tall and hefty, who
had presented elsewhere with seizure‑like activity. The venous
blood glucose during seizure was 40 mg/dl. On probing, the
patient recounted several episodes of hypoglycemia for the last
few months. Most of them occurred in the postprandial period,
but a few were in the fasting state. The patient was diagnosed
to have Sjogren’s syndrome 2 years back. On examination, she
had mild acanthosis nigricans. Her hemoglobin A1C was 6.1%.
Our initial differentials were autoimmune hypoglycemia and
reactive hypoglycemia of prediabetes. Since hypoglycemia was
recurrent, was severe, and happened in a patient with a known
systemic autoimmune disease, we considered autoimmune
hypoglycemia as the chief possibility. We subjected the patient
to a standard 72‑h supervised fast. The patient did not develop
hypoglycemia during the first 48 h. Even more puzzling was
the absence of ketonuria even after 48 h of fasting. Since this
finding defied basic biochemistry, we reconfirmed the absence
of surreptitious calorie intake.
As the supervised fast did not allow us to exclude endogenous
hyperinsulinism, we did an extended glucose tolerance test
with 100 g of glucose. Four hours after ingesting glucose, the
patient developed hypoglycemia. The critical sample showed
endogenous hyperinsulinism and absence of anti‑insulin
antibodies. Thus, we made the diagnosis of prediabetes
leading to reactive hypoglycemia. The insulin resistance and
the resultant “endogenous hyperinsulinism” perhaps explain
the lack of ketonuria during fasting.
In the evaluation of hypoglycemia, the order of testing‑supervised
fast versus meal challenge is not emphasized.[1]  Of the causes
572 Indian Journal of Endocrinology and Metabolism  ¦  Volume 22  ¦  Issue 4  ¦  July-August 2018
This is an open access journal, and articles are distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to
remix, tweak, and build upon the work non-commercially, as long as appropriate credit
is given and the new creations are licensed under the identical terms.
Access this article online
Quick Response Code:
Website:
www.ijem.in
DOI:
10.4103/ijem.IJEM_125_18
How to cite this article: Padmanaban V, Prakash SS. Strain, diet, and
gender influence the role of miR155 in diabetes mellitus. Indian J Endocr
Metab 2018;22:570-2.
© 2018 Journal of Clinical Imaging Science | Published by Wolters Kluwer - Medknow
of postprandial hypoglycemia, reactive hypoglycemia is most
common because of the sheer number of prediabetes patients.
In our attempt to abide by the dictum of Occam’s razor in
medicine  –  of eschewing a double diagnosis when one would
suffice (autoimmunity and reactive hypoglycemia vs. autoimmunity
alone), we committed the fallacy of base rate neglect.
We ignored prior probabilities  (of reactive hypoglycemia)
when confronted with specific details about the patient (with
a systemic autoimmune disease). As Tversky and Kahneman
show in their seminal paper,[2] this bias is common and has
profound implications for medicine  –  common problems
are more common even in patients with rare diseases.
As an extension, a test that teases out the more common
problem should be done first. Thus, in obese patients with
hypoglycemia, it is preferable to do an extended glucose
tolerance test first before the 72 h fast. This also has several
practical advantages: glucose tolerance test is easier to do, does
not require admission, and is well “tolerated” by the patients.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Karthik Balachandran, Adlyne Reena Asirvatham, Shriraam Mahadevan
Department of Endocrinology, Sri Ramachandra Medical College and Research
Institute, Chennai, Tamil Nadu, India
Address for correspondence:
Dr. Shriraam Mahadevan,
Department of Endocrinology, Sri Ramachandra Medical College and
Research Institute, Chennai, Tamil Nadu, India.
E‑mail: mshriraam@gmail.com