Type 2 diabetes pathogenesis involves multiple complex pathophysiological abnormalities that result in hyperglycemia. Key factors include insulin resistance caused by genetic and environmental factors like obesity, and beta cell dysfunction caused by glucotoxicity, lipotoxicity, and other stresses that impair insulin secretion and lead to loss of beta cell function and mass over time. Genetic factors also contribute significantly, as seen in familial risk and heritability studies, though identifying specific genes has been challenging due to the polygenic nature of type 2 diabetes.

1. Type 2 diabetes pathogenesis
Diletta Rosati
Samaneh Gholami
Kristina Zguro
Ali Hakimzadeh

2. INTRODUCTION

3. EPIDEMIOLOGY
 T2D is one of the major challenges to human
health in the 21st century.
 Has a great economic impact on countries and
national health systems.
 The majority of countries spend 5-20% of
their total health expenditure on diabetes.

4. Normal glucose homeostasis:
• Hepatic glucose output
• Glucose uptake and utilization by peripheral tissues
• Action of insulin and glucagon on glucose metabolism
HOMEOSTASIS

5. Insulin
• Immediate release of insulin

6. Insulin signaling
 Insulin increase the rate of glucose transport into certain cells in the body

7. Natural History of TDM2
• T2D is a progressive disease that develops in stages.
• Its natural history probably begins 10–20 years before
its clinical onset

8. Factors
• Multiple factors involved in the genesis of T2D.

9. INSULIN RESISTANCE

10. Multiple, Complex Pathophysiological Abnormalities in T2DM
peripheral
glucose
uptake
hepatic
glucose
production
pancreatic
insulin
secretion
pancreatic
glucagon
secretion
gut
carbohydrate
delivery &
absorption
HYPERGLYCEMIA
?
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
_
_
+
renal glucose
excretion

11. INSULIN RESISTANCE
Lower biological activity of
Insulin in its different
metabolic actions for a
certain concentration;
Inability of tissues to respond
to normal levels of insulin

12. All processes malfunctions result in IR;
Receptor phosphorylation,
receptor number,
GLUT-4,
IRS-1 phosphorylation, etc
INSULIN RESISTANCE

13. Cause of IR
Strong genetic component
o Identical twins >90% concordant
o Contribution of Epigenetics
Environment Important
o Increased incidence over last century
o Lifestyle, exercise, habits
o Diet
o Most commonly associated with obesity (>80% of cases)

14. IR genes
• Directly associated with lower
glucose uptake
• Insulin receptor substrate gene
• Phosphoinositide 3-kinase gene
• Explaining the obesity-type 2
diabetes relationship
• β-3 adrenergic receptor gene
• Tumor necrosis factor alpha gene
• Peroxisome proliferator-activated
receptor gene
• Adipocytokines in obesity
• Leptin gene
• Resistin gene
• Adiponectin gene
• Lipid metabolism
• Lipoprotein lipase gene
• Fatty acid-binding protein gene
• The thermogenesis obesity relationship
• Uncoupling protein gene

15. IR in liver, muscle and adipose tissue
Adapted from: pathogenesis of T2DM, Pilar Durruty et al, Elsevier feb2019
Increase in FFA
Or
Lipoatrophy

16. IR and OBESITY
Adapted from: Treatment of type 2 Diabetes, Fuad Alseraj, InTech open 2015
The most critical factor in the e
mergence of metabolic factor in
IR is obesity.

17. β-CELLS DISFUNCTION

18. Decline of ꞵ cell function
 There is a progressive deterioration in β-cell function over time in type 2 Diabetes mellitus
 The pancreatic islet function was found to be about 50% of normal at the time of diagnosis (as
indicate by UK-PDS)
 The reduction in function probably commencing 10-12 yr before diagnosis and aggravated by
increasing fasting plasma glucose level
 With a corresponding decline in β-cell function, was found glycated haemoglobin levels to
increase over time (level of HbA1c 6.5% or higher)

19. Insulin secretion defect in DM2
The defect of insulin secretion in DM2 is related to two confounding components :
 Insulin deficiency
DM2 is characterized by an increased fasting ratio of proinsulin to total immunoreactive insulin indicating a
reduced processing of proinsulin, which correlates with β-cell dysfunction and is predictive of disease development
 β-cell secretory defect
Studies (BMC Biology Cantley & M.Ashcroft) with modest sample sizes (n = 5 to 17 cases) have clearly shown that
glucose-stimulated insulin secretion (GSIS) is defective in islets from T2D donors, relative to non-diabetic donors.
In two of these studies, islets from T2D donors responded normally to non-glucose stimuli ( eg. Arginine) ,
suggesting defective GSIS in these cohorts is likely due to impaired glucose-sensing (stimulus-secretion coupling)
rather than a loss of insulin content or a constitutive defect in insulin exocytosis

20. Insulin secretion defect in DM2
 Decreased β-cell mass
Diminished proliferation, or increased apoptosis or
both will result in lower β-cell mass
There is evidence that increased β-cell apoptosis in
the Zucker diabetic fatty rat, an animal model of
DM2, underlies the decreased β-cell mass seen in
these animals.

21. Insulin secretion defect in DM2
The study by Butler et al.(4)
Relative β-cell volume increased by 50%
in obese compared with lean nondiabetic
Relative β-cell volume was decreased in
obese IGT and more in obese DM2

22. Factors for progressive loss of β-cell function and mass
o Glucotoxicity
o Lipotoxicity
o Proinflammatory cytokines and leptin
 Adipocyte-secreted factors
Increased cell nutrients
Innate immune system and
autoimmunity
o Islet cell amyloid
o Linkage of reduced β-cell mass and
dysfunction

23. Factors for progressive loss of β-cell function and mass
GLUCOTOXICITY
Pathway of oxidative stress production Reduction of insulin biosynthesis and
secretion by oxidative stress

24. Factors for progressive loss of β-cell function and mass
 Elevated levels of free fatty acids can have many
deleterious effects on β-cells:
Decreased glucose-stimulated insulin secretion
Impaired insulin gene exepression
Increased synthesis of ceramides
Activation of the oxidative stress
Increased β-cells inflammation
β-cell apoptosis

25.  Adipocyte – secreted factors
Leptin
TNF-α
IL-6
IL-1Ra

26. Factors for progressive loss of β-cell function and mass
 Increased in cell nutrients
Increasing glucose concentrations induce β-cell production of IL-1β leading to β cell apoptosis
Both IL-1β and ROS activate NF-κB an important mediator of inflammatory responses
Increased FFAs concentration may act directly on β-cells or activate the innate immune system
 Innate immune system and autoimmunity
• In addition to the endocrine activity of the adipocytes macrophages and endothelium may contribute to
increasing serum levels of IL-1β, IL-6, TNF-α
• Increasin apoptotic cells can provoke an immune response
• Some DM2 patients may show mobilization of T cells reactive to β-cell antigens, culminating in
autoimmune destruction of β-cells

27. Factors for progressive loss of β-cell function and mass
 Islet cell amyloid
Amylin or Islet amyloid polypeptide (IAPP) is a 37-
residue peptide hormone cosecreted with insulin
Amylin contributes to glycemic control, functioning
as a synergistic partner to insulin.
Impaired N-terminal processing of proIAPP is an
important factor initiating amyloid formation and β-
cell death

28. Factors for progressive loss of β-cell function and mass
 2 possible explanations account for the impaired β-cell function consequent to
decreased β-cell mass:
Increased insulin demand on residual β-cells per se
Hyperglycemia consequent to decreased β-cell mass driving the impairment in
β-cell function

29. Genetics in T2D

30. Genetics and T2D
 Individuals with a positive family history are about 2-6 times more likely to develop
T2D than those with a negative family history
– Risk ~40% if T2D parent; ~80% if 2 T2D parents
 Higher concordance for MZ VERSUS DZ twins
 Has been difficult to find genes for T2D
− Late age at onset
− Polygenic inheritance
− Multifactorial inheritance

31. Challenges in Finding Genes
 Inadequate sample sizes
– Multiplex families
– Cases and controls
 Difficult to define the phenotype
 Reduced penetrance
– Influence of environmental factors
– Gene-gene interactions
 Variable age at onset
 Failure to replicate findings
 Genes identified have small effects

32. CAPN10 – NIDDM1
 Chromosome 2q37.3
– Encodes an intracellular calcium-dependent cytoplasmic protease that is ubiquitously
expressed
• May modulate activity of enzymes and/or apoptosis
– Likely involves insulin secretion and resistance
– Stronger influence in Mexican Americans than other ethnic groups
• Responsible for ~40% of familial clustering
– Genetic variant: A43G, Thr50Ala, Phe200Thr
PPARγ
 Chromosome 3p25
– Transcription factors that play an important role in adipocyte differentiation and
function
– Is associated with decreased insulin sensitivity
– Target for hypoglycemic drugs
– Genetic variant: Pro12Ala, Pro is risk allele (common)
– Variant is common
– May be responsible for ~25% of T2D cases

33. ABCC8 and KCNJ11
 ATP-binding cassette, subfamily C member 8 (chromosome
11p15.1)
 Potassium channel, inwardly rectifying, subfamily J, member 11
(chromosome 11p15.1)
– ABCC8 encodes the sulfonylurea receptor (drug target )
– Is coupled to the Kir6.2 subunit (encoded by KCNJ11 – 4.5 kb apart
& near INS )
– Part of the ATP-sensitive potassium channel
• Involved in regulating insulin and glucagon
• Mutations affect channel’s activity and insulin secretion
– Site of action of sulfonylurea drugs
– Genetic variants: Ser1369Ala & Glu23Lys, respectively

34. TCF7L2
 Transcription factor 7-like 2 (chromosome 10q25)
– Related to impaired insulin release of glucagon-like peptide-1 (islet
secretagogue), reduced β-cell mass or β-cell dysfunction
• Stronger among lean versus obese T2D
– 10% of individuals are homozygous have 2-fold increase in risk
relative to those with no copy of the variant
– Responsive to sulfonylureas
– Genetic variant: rs7901695 and others in LD

35. GWAS New Loci Identified
 FTO – chr 16q12
– Fat mass and obesity associated gene
– Governs energy balance; gene expression is regulated by feeding and fasting
 HHEX/IDE – chr 10q23-24; near TCF7L2
– HHEX - Haematopoietically expressed homeobox
• Transcription factor in liver cells
– IDE - Insulin degrading enzyme
• Has affinity for insulin; inhibits IDE-mediated degradation of other substances
 CDKAL1 – chr 6p22
– Likely plays role in CDK5 inhibition and decreased insulin secretion
 IGF2BP2 – chr 3q28
– Regulates IGF2 translation; stimulates insulin action
 CDKN2A/B – chr 9p21
– Plays role in pancreatic development and islet proliferation

36. MODY Genes
Type Gene Locus Protein # Mutations % MODY
MODY1 HNF4A 20q12-q13.1 Hepatocyte nuclear factor 4-
alpha
12 ~5%
MODY2 GCK 7p15-p13 Glucokinase ~200 ~15%
MODY3 HNF1A 12q24.2 Hepatocyte nuclear factor 1-
alpha
>100 ~65%
MODY4 IPF1 13q12.1 Insulin promotor factor-1 Few
MODY5 HNF1B 17cen-q21.3 Hepatocyte nuclear factor 1-
beta
Few <3%
MODY6 NEUROD1 2q32 Neurogenic differentiation
factor 1
Few
 All MODY genes are expressed in the pancreas, and play a role in:
– The metabolism of glucose
– The regulation of insulin or other genes involved in glucose transport
– The development of the fetal pancreas

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