1. Genetic syndromes of severe insulin resistance include rare monogenic defects that result in conditions like leprechaunism (Donohue syndrome) and Rabson-Mendenhall syndrome. These are caused by mutations in the insulin receptor gene that produce nonfunctional or impaired insulin receptors. 2. Leprechaunism is the most severe form, characterized by intrauterine growth retardation, fasting hypoglycemia, and death in the first 1-2 years of life. It results from autosomal recessive mutations that create inactive insulin receptors. Rabson-Mendenhall syndrome is also autosomal recessive but milder, causing growth abnormalities and androgen excess.

1. Syndromes of Severe Insulin
Resistance
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2. I. Genetic Syndromes of Severe Insulin Resistance
 the most prevalent endocrine derangements in the world
 diabetes mellitus,
 atherosclerosis,
 nonalcoholic fatty liver disease,
 and ovulatory dysfunction
2
It is most commonly found in those with obesity but may also occur in an
unusually severe form in rare patients with monogenic
defects

3. II. Definition and Prevalence of Severe IR
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“a state (of a cell, tissue, or organism) in which a greater than normal
amount of insulin is required to elicit a quantitatively normal response”
Insulin resistance may be the underlying
cause of diabetes mellitus type 2 was first
advanced by Prof. Wilhelm Falta and
published in Vienna in 1931
THIS theory confirmed by Sir Harold
Percival Himsworth of the University
College Hospital Medical Centre in
London in 1936.
Genetics
&
Aging
Acquired:
• Central
obesity
• Sedentary
lifestyle
• High fat diet
• Medications

4. Obesity and less sensitive to insulin
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There are genetic insulin resistance and diet-induced insulin
resistance. Obesity is the most common cause of insulin resistance.

6. 6Mechanisms:
Infiltrating macrophages secret TNFα. TNFα activates JNK and IκB Kinase
(IKK), which phophorylate IRS-1, hence inhibits insulin receptor signaling.

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11. Monogenic diabetes
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12. Introduction
 Human genome contains more than 3
billion base pairs
 20-25000 genes are believed to code for
proteins
 Single gene defects can lead to diabetes –
independent of environmental influences
 Dominant ,recessive or denovo
 Most are due to mutations in genes
which regulate βcell function
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14. Mutations in the insulin receptor gene
 The first defects in the INSR were reported in 1988
 more than 100 allelic
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1.
Rare and severe autosomal recessive
presenting in the first decade of life
Donohue syndrome
Rabson Mendenhall syndrome (RMS)
fasting hypoglycemia,
Postprandial hyperglycemia,
extreme hyperinsulinemia
2. autosomal dominant
 Type A insulin resistance
retarded linear growth, impaired
muscle and dipose tissue
development,
and overgrowth sex ormone-
dependent tissues
such as genitalia and nipples,
and of other tissues including
hair, skin, and viscera

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17. Why diagnose
monogenic
diabetes
 To elucidate the pathophysiology
 Changes the treatment
 diagnosis has implications for other family members
often correcting their diagnosis, prognosis and treatment
as well as allowing appropriate genetic counselling
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Insulin receptor

19. Location: 19p13.3-p13.2
Exon count: 22
Two insulin receptor mRNA
transcripts resulting from
alternative splicing of exon
11 in the receptor gene are
expressed in a highly
regulated tissue-specific
fashion
19
Insulin receptor gene

20.  INSULIN ACTS ON SPECIFIC RECEPTORS
LOCATED ON THE CELL MEMBRANE OF
PRACTICALLY EVERY CELL, BUT THEIR
DENSITY DEPENDS ON THE CELL TYPE:
LIVER AND FAT CELLS ARE VERY RICH.
 THE INSULIN RECEPTOR IS A RECEPTOR
TYROSINE KINASE (RTK) WHICH IS A
HETEROTETRAMERIC GLYCOPROTEIN
CONSISTING OF 2 EXTRACELLULAR Α
2 TRANSMEMBRANE Β SUBUNITS LINKED
TOGETHER BY DISULFIDE BONDS,
ORIENTING ACROSS THE CELL
AS A HETERODIMER
 IT IS ORIENTED ACROSS THE CELL
MEMBRANE AS A HETERODIMER.
 THE Α SUBUNITS CARRY INSULIN
BINDING SITES, WHILE THE Β SUBUNITS
HAVE TYROSINE KINASE ACTIVITY.
INSULIN RECEPTOR; INSR
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Pathology
insulin resistance
leprechaunism,
lipodystrophies,
Rabson-Mendenhall syndrome
type B insulin resistance syndrome

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24. Rabson–Mendenhall syndrome
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a rare autosomal recessive disorder
caused by mutations in the insulin receptor gene
INSR, ASN42LYS
INSR, ARG1027TER
INSR, IVS4AS, A-G, -2
INSR, 8-BP DEL, NT2480
To date, 19 different mutations in the INSR gene have
been reported in patients with RMS.

25. Symptoms
 growth abnormalities of the head, face
and nails,
 acanthosis nigricans
 androgen excess,
 absence of obesity
 massively raised insulin concentrations
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27. Inheritance Pattern
affects males and females in equal numbers
Fewer than 50 cases have been reported in the medical
literature

28. Subjects
The proband (RMS-1) was an 11-year-old Chinese girl, and the only child of
Healthy parents who had no family history of diabetes mellitus or other hereditary
diseases.

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33. Standard Therapies
 Treatment
 There is no specific treatment
 The treatment of the disorder is directed toward the specific symptoms
 Affected individuals may receive high doses of insulin or insulin sensitizers,
but in most cases this therapy ultimately proves unsuccessful.
 Treatment may require the coordinated efforts of a team of specialists.
 Pediatricians, surgeons, dental specialists, and other health care
professionals may need to systematically and comprehensively plan an
affected child’s treatment.
 Genetic counseling may be of benefit for affected individuals and their
families. Other treatment is symptomatic and supportive.
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35. 35
Growth charts for the female (A) and male
(B)
siblings. The characteristic growth
retardation of the
RM syndrome is shown. The arrow
indicates when leptin
therapy began.

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38. Leperchunism Donohue syndrome
leprechaun; (in Irish folklore) a small,
mischievous sprite.
an insulin receptor with greatly
impaired functionality.
intrauterine growth retardation,
fasting hypoglycemia, and death
within the first 1 to 2 years of life
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39. Genetics
an autosomal recessive genetic disorder
mutations occurs within
on the short arm chromosome 19 (19p13.2) within
the coding sequence of the INSR gen
production of inactive receptor molecules
Known mutations
a nonsense mutation that resulted in a frame shift
a single missense mutation
and in the milder form; a single codon change that
altered isoleucine to methionine in the receptor
protein
Affected Populations
In reported cases, leprechaunism has occurred twice
as often in females as in males (F2:M1). More
than 50 cases have been reported in the medical
literature.

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Diagnosis
The diagnosis of leprechaunism may be confirmed by a thorough clinical evaluation, a
detailed patient history, identification of characteristic symptoms and physical findings.
The diagnosis requires measurement of insulin levels, with a blood test, and confirmation
of defective insulin binding on the cells known as fibroblasts.
Prenatal diagnosis is possible through analysis of DNA obtain through a procedure known
as amniocentesis. During amniocentesis, a sample of fluid that surrounds the developing
fetus (amniotic fluid) is removed and studied. DNA obtained from amniotic cells is
analyzed through a test known as polymerase chain reaction (PCR). PCR, a laboratory
technique that many have described as a form of “photocopying,” enables researchers to
enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely
analyze DNA and more easily identify genes and genetic changes (mutations). In
leprechaunism, polymerase chain reaction is used to identify mutations to the insulin
receptor gene.

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