Complete insight into the molecular basis of diabetes based on Principle of Molecular Medicine book

1. Molecular Basis of Diabetes
By: Dr. Fatemeh Ramezani
Assistant professor of Clinical Biochemistry
Department of Molecular Medicine
Faculty of Advanced Medical Science
Tabriz University of Molecular Medicine

2. Worldwide trends in diabetes since 2014
 With an 8.5% global prevalence of diabetes in 2014; various
estimates suggest that the number of affected people will be risen
from 422 million to 642 million in the world by 2040.
 Age-standardised adult diabetes prevalence in 2014 was lowest in
northwestern Europe, and highest in Polynesia and Micronesia, at
nearly 25%.
 3.78 million cases of DM in Iran in 2009. This number is expected to
rise to 9.24 million cases by 2030.
Worldwide trends in diabetes since 1980, NCD Risk Factor Collaboration
(NCD-RisC), Lancet, 2016.

3. Diabetes mellitus
 Is characterized by:
fasting and postprandial hyperglycemia.
 Type 1 diabetes occurs secondary to autoimmune destruction of the
insulin-secreting pancreatic β-cells.
 Type 2 diabetes results from a deficiency of insulin action secondary to a
combination of insulin resistance and relative β-cell dysfunction.
 A genetic contribution to the etiology of the diseases, but monozygotic
twin have indicated that environmental factors also contribute to their
etiology.
 In general, it is complex and polygenic diseases.

4. Metabolic changes in diabetic ketoacidosis
The Genetic Landscape of Diabetes Last Updated: 2004 Jul 7 National Center for Biotechnology Information
(US) Bethesda (MD) Laura Dean • Jo McEntyre

5. Diagnosis and Classification of Diabetes Mellitus,
American Diabetes Association, Diabetes Care,
2014.

6. GENETICS OF TYPE 1 DIABETES MELLITUS
 Type 1 diabetes often presents abruptly with:
 marked hyperglycemia, polyuria, and ketoacidosis, which occur as a
result of insulin deficiency.
 The autoimmune-mediated destruction of pancreatic β-cells is
characterized by two features, autoantibodies and insulitis.
 Autoantibodies are directed against a variety of β-cell
antigens, including:
 insulin, glutamic acid decarboxylase (GAD65 and 67), and a catalytically
inactive member of the transmembrane protein tyrosine phosphatase
family (IA-2).

8. Human leukocyte antigen

9. PRINCIPLES OF MOLECULAR MEDICINE, second edition, EDITED BY MARSCHALL S. RUNGE

10. The Genetic Landscape of Diabetes Last Updated: 2004 Jul 7 National Center for Biotechnology Information
(US) Bethesda (MD) Laura Dean • Jo McEntyre

11. The original association with class-I molecules was likely because of the nonrandom
association of class-I alleles with the class-II alleles (linkage disequilibrium).
Immunogenetics of type 1 diabetes mellitus, Michael P. Morran, Molecular Aspects of Medicine, 2015.

12. Second susceptibility locus,
The insulin gene locus on chromosome 11p15.5

13. Immunogenetics of type 1 diabetes mellitus, Michael P. Morran, Molecular Aspects of Medicine, 2015.

14. ID-TEC mice develop spontaneous diabetes within
4 weeks after birth
Thymus-specific deletion of insulin induces autoimmune diabetes, Yong Fan, The EMBO Journal 2009.

15. Autoantigen Epitope Spreading in T1DM
Immunogenetics of type 1 diabetes mellitus, Michael P. Morran, Molecular Aspects of Medicine, 2015.
Epitope spreading begins once the immune system is triggered within the pancreas, leading to
the processing and presentation of self-antigens. As β-cell destruction takes place, multiple self-
antigens become targets of the immune system. During this process, insulin is thought to be the
first antigenic target, followed by other β-cell associated components, such as glutamic-acid
decarboxylase 65 (GAD65) and islet-cell antigen-2 (IA-2) and ZnT8.

16. Cytotoxic T-lymphocyte-
associated 4 (CTLA4)
Protein tyrosine phosphatase,
non-receptor type 22
(PTPN22) or (LYP)
Both of them downregulates
T-cell activation.

17. Wolfram Syndrome
 Wolfram and Wagener in 1938.
 A progressive neurodegenerative disease
with an autosomal-recessive fashion.
 The acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic
atrophy, and deafness).
 Early onset (generally age <15 yr) of diabetes and optic atrophy are
necessary for the diagnosis.
 In MRI have seen atrophy of the optic nerves and neurodegeneration
in the lateral geniculate nucleus, basis pontis, and hypothalamic nuclei.

18. The gene responsible for Wolfram Syndrome
 WFS1 gene on short arm of chromosome 4 (4p16.3) encodes a
novel approx 100-kDa protein, wolframin.
 Wolframin is an integral membrane glycoprotein, as a calcium
channel or as a regulator of calcium channel activity.
 In the pancreas, wolframin is present in β-cells and, to a much
lesser extent, α-cells.

19. WFS1 controls steady-state levels of ATF6α protein and activation
Wolfram syndrome 1 gene negatively regulates ER stress
signaling in rodent and human cells, Sonya G. Fonseca, the
journal of clinical investigation, 2010

20. Schematic model of the etiology of type 2
diabetes mellitus
PRINCIPLES OF MOLECULAR MEDICINE, second edition, EDITED BY MARSCHALL S. RUNGE

21. The hyperbolic insulin sensitivity/secretion curve

22. Mitochondrial Diabetes Mellitus
 Mitochondrial DNA is inherited maternally.
 Encodes 13 polypeptide subunits involved in oxidative
phosphorylation and the respiratory pathway, 22 transfer RNAs
(tRNAs), and 2 ribosomal RNAs.
 An A/G exchange at nucleotide 3243 in
the mitochondrial tRNALeu(UUR).
 This mutation alters both tRNALeu(UUR)
synthesis and mitochondrial protein stability.

23. Maturity Onset Diabetes of the Young
 MODY is a subtype of diabetes that is monogenic.
 MODY is characterized by an early age of onset of diabetes and
an autosomal-dominant mode of inheritance.
 Disease onset often occurs between ages 9 and 13 and typically,
occurs before age 25.
 Six variants of MODY, MODY1–6, have been characterized.

24. MODY Genes
PRINCIPLES OF MOLECULAR MEDICINE, second edition, EDITED BY MARSCHALL S. RUNGE
HNF, hepatocyte nuclear factor; MODY, maturity onset diabetes of the young. Adapted with
permission from Mitchell SMS, Frayling TM. The role of transcription factors in maturity-onset
diabetes of the young. Mol Genet Metab 2002;77:35–43.

25. Insulin Gene
 Six different mutations that affect insulin processing and
action, but these mutations are rare.
 Three of these mutations alter the primary sequence of the A-
or B chain of insulin.
 These mutations affect insulin binding to its receptor and,
thus, decrease the efficacy of insulin.
 An association of the class-III allele the insulin VNTR with
increased risk for type 2 diabetes.

26. Insulin Receptor
Mechanism of action of insulin, Chhabra, 2014

27. Insulin Receptor Gene
 Insulin receptor mutations were associated with specific
syndromes of extreme insulin resistance, including
leprechaunism, Rabson–Mendenhall syndrome, and type-A
extreme insulin resistance.
 These syndromes differ phenotypically because of different
degrees of insulin resistance.
 The varying degree of insulin resistance in these different
syndromes is determined both by the number of mutant
alleles inherited as well as the severity of the mutations.

28. Insulin Receptor Gene….
 Leprechaunism is associated with the greatest degree of insulin
resistance ,intrauterine and postnatal growth retardation,
dysmorphic facies, lipoatrophy, acanthosis nigricans (a cutaneous
manifestation of insulin resistance), and death in early infancy.
 Rabson–Mendenhall presents in early childhood and is
characterized by insulin-resistant diabetes mellitus, abnormal facies,
dental dysplasia, thickened nails, hirsutism, precocious puberty, and
acanthosis nigricans.
 Type-A insulin resistance is characterized by extreme insulin
resistance, albeit of lesser degree than above two syndromes, mildly
impaired glucose homeostasis and acanthosis nigricans,
hyperandrogenism, hirsutism, and polycystic ovaries.

29. Leprechaunism
the typical "elfinlike" facies of leprechaunism with
hirsutism, large, low-set ears, broad nasal tip and
flared nares, and thick lips, reduced subcutaneous
fat, prominent nipples, a distended abdomen, large
external genitalia, and rectal prolapse.
Rabson–Mendenhall
acanthosis nigricans

30. Schematic representation of glucose-stimulated insulin secretion
by the pancreatic β-cell
PRINCIPLES OF MOLECULAR MEDICINE, second edition, EDITED BY MARSCHALL S. RUNGE

31. Candidate Genes for Late-Onset Type 2 Diabetes
Gene Name Mutation Characteristics
Sulfonylurea receptor
(SUR1)
A nucleotide
transition in intron 16
(-3c to t)
Is associated with increased susceptibility to
type 2 diabetes in various Caucasian
populations.
Inwardly rectifying K+
channel subfamily 6.0
(KIR6.2)
A glutamic acid to
lysine substitution at
codon 23 (E23K)
The variant protein altered the probability of
the channel being in the open vs closed state
and the ATP sensitivity of the channel.
consequence of this is to shift the physiological
glucose dependence of channel activity to a
higher glucose concentration and inhibit insulin
secretion.
Peroxisome
proliferator-activated
receptor ( PPAR)-γ
Substitution of
leucine for proline at
codon 467 and
methionine for valine
at codon 290
Both of these mutations abrogate ligand-
induced transactivation of PPAR-γ and result in
insulin resistance with early-onset diabetes and
hypertension and low high-density lipoprotein
levels in association with elevated triglyceride
levels.

32. When to consider a diagnosis of MODY at the presentation of diabetes, Agata Juszczak, British Journal of General Practice, 2016

33. CLINICAL IMPLICATIONS
 Understanding the molecular basis of type
2 diabetes will facilitate the development of
new therapeutic modalities.
 In appropriate individuals, aggressive preventive measures might
be instituted.
 Moreover, type 2 diabetes can be subclassified based on the
predisposing genes present in a patient,
 That subclassification can be used to direct therapeutic
interventions.