Diabetes Ecogenetic

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Diabetes Ecogenetic

• By
• Nana Aisha Garba

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Overview

• A group of metabolic diseases resulting from a
  relative or absolute lack of insulin.
• Insulin is a hormone produced by the pancreatic
  ß- cells of the Islet of Langerhans.
• It is responsible for glucose uptake into cells.
• Diabetes is characterized by high blood glucose
  level.

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Epidemiology

• There are an estimated 143 million people
  worldwide with the disease, almost five times
  more than estimates of ten years ago
• Of the 13 million people afflicted in the United
  States only half are clinically diagnosed.
• The disease is considerably more common among the
  elderly and strikes African-, Mexican- and Native
  Americans at 1.73 times the rate for that of
  non-Hispanic whites.
• 7th leading cause of death in the United States
• Annual mortality rate of 54,000.
• Lifetime risk for an American adult of developing
  diabetes
• 5-7 -Type 2
• 0.5 -Type 1
• Median Age Range
• 50 gt55 years
• Type onset is around 20 yearsType 2 onset gt40
  years

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Types of Diabetes

• Diabetes may be either Primary or Secondary.
• Primary Diabetes 3 types
• - Non Insulin dependent (Type 2)
• - Insulin dependent (Type 1)
• - Gestational diabetes
• Secondary (causes) Diabetes Mellitus
  Hemochromatosis, Chronic pancreatitis, Hormonal
  tumors, Drugs, and some genetic disorders,
  Pregnancy and Pcos.

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Type 1 Diabetes

• Formerly known as Juvenile onset Dm or Insulin
  dependent Dm (IDDM)
• Usually first diagnosed in children, teenagers,
  or young adults
• The beta cells of the pancreas no longer make
  insulin because the bodys immune system has
  attacked and destroyed them.
• The etiology of type 1 diabetes is still unknown,
  but it is believe that autoimmune , genetic, and
  environmental factors are involved

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Insulin is present and is taken into the cell to
facilitate proper glucose uptake and metabolism.


In Type I diabetes, insulin is not produced so,
there is nothing to signal the cells to take in
glucose and metabolize it.
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Type 2 Diabetes

• Formerly called adult-onset diabetes or
  noninsulin-dependent diabetes (NIDDM).
• It is the most common form of diabetes.
• Onset may be at any age even childhood
• Usually begins with insulin resistance, a
  condition in which fat, muscle, and liver cells
  do not use insulin properly.
• At first, the pancreas keeps up with the added
  demand by producing more insulin. In time,
  however, it loses the ability to secrete enough
  insulin in response to meals.
• Being overweight and inactive increases the
  chances of developing type 2 diabetes.

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Insulin is present But the signal for proper
glucose uptake and metabolism is lost. The
problem could be in the insulin itself or in any
one of the proteins involved in glucose uptake
and metabolism
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Gestational Diabetes

• Some women develop gestational diabetes during
  the late stages of pregnancy.
• Although this form of diabetes usually goes away
  after the baby is born, a woman who has had it is
  more likely to develop type 2 diabetes later in
  life.
• Gestational diabetes is caused by the hormones of
  pregnancy or a shortage of insulin.

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Symptoms of Diabetes

• The Classic triad of diabetes is Polydipsia,
  polyphagia and polyuria.
• Other symptom include Fatigue dehydration,
  weight loss, tremulousness, sweating, dizziness,
  visual impairment and susceptibility to skin ,
  bladder and vaginal infections as well as leg
  ulcers or slow healing ulcers.

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Type 1Diabetes Mellitus Genetics

• 5 of Diabetics have Type 1 diabetes.
• Familial 6 of children or first order relatives
  of diabetics with type1 diabetes develop disease.
• Cumulative concordance among identical twins is
  70
• About 5-10 of North American diabetics have type
  1
• There are two susceptibility genes 1) is in the
  region encoding for class II antigens of the MHC
  on chromosome 6p21 (HLA-D)
• 2) the insulin gene (INS) region.
• The HLA region is a cluster of genes on
  chromosome 6.

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Genetic susceptibility

• The genes encode glycoproteins that are found on
  the surfaces of most cells and help the immune
  system to distinguish between self and non-self
  (e.g., bacteria, viruses).
• In Type 1 diabetes HLA alleles may increase the
  risk of diabetes, have no effect, or even be
  protective.
• The HLA genes encode proteins called major
  histocompatibility complex (MHC), and there are
  two main classes of MHC proteins, both of which
  display chains of amino acids.
• The chains are called antigens, and immune cells
  (called T cells) analyze them. Class I MHC
  present chains from inside cells, whereas MHC
  class 2 present chains from outside the cells.

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Genetic susceptibility Conts

• If T cells bind to the chain presented on an MHC,
  the T cell immediately orchestrates powerful
  attacks by the body's other immune cells.
• There are many different alleles of the HLA
  genes, leading to many different variants of MHC
  proteins and allowing a variety of chains to be
  presented to cells.
• The inheritance of particular HLA alleles can
  account for over half of the genetic risk of
  developing type 1 diabetes.
• Class II MHC proteins are most strongly linked
  with diabetes, and their encoding genes are
  called HLA-DR, HLA-DQ, and HLA-DP.
• In the general population, only half of the
  people inherit a copy (allele) of DR gene called
  DR3 and DR4, and less than 3 of the people have
  two alleles.
• However, in type 1 diabetes at least one allele
  of DR3 or DR4 is found in 95 of Caucasians, and
  individuals with both DR3 and DR4 are
  particularly susceptible to type 1 diabetes.
  Conversely, the DR2 allele is protective.

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Environmental Susceptibility Factors Type1

• Geographical
• Finnish children have 60-70 fold increased risk
  of developing the disease versus Korean children
• Emigrants from Japan, Israel, and Canada, assume
  a risk closer to the destination country than the
  country of origin.
• Viruses
• Viruses may cause mild B-cell injury resulting in
  autoimmune injury in HLA susceptible individuals
  caused by unmasking of previously sequestered
  antigens
• Enteroviruses, may trigger the beta-cell damaging
  process in a considerable proportion of patients.
• Immune response may develop against a viral
  protein sharing amino acid sequences with a beta
  cell protein
• Endogenous retroviral genome has been discovered
  in diabetic islets serving as a superantigen-may
  serve as a trigger, precipitator, or marker for
  diabetes.
• Others
• Dietary putative etiological factors Many
  studies indicate an association between early
  Antigenic exposure to cow's milk products lt4
  months of age have 1.5 fold increased risk. Vit D
  is another factor which requires more study
• Chemical toxinsPentamidineVacor

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Case study

• A prospective study was conducted (Olmos et al)
  on 49 non-diabetic identical twins of
  recently-diagnosed Type 1 (insulin-dependent)
  diabetic patients for up to 24 years (median 9
  years).
• During this time 15 developed Type 1 diabetes.
  Actuarial analysis indicates that by 12 years 34
  of the twins will have developed Type 1 diabetes
  and that thereafter only another 2 will do so.
• Inevitable bias in ascertainment of the twins
  makes it likely that the true figure is less.
• The conclusion of the study was that factors
  which are not genetically determined must be
  important in the pathogenesis of the disease.
• The rates of developing Type 1 diabetes in the
  co-twins declines sharply in the years after
  diagnosis of the index twin, which suggests that
  the initiation of the process leading to Type 1
  diabetes occurs within a finite, and not a
  prolonged, period.

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Diabetes Mellitus Type 2

• Not linked to HLA genes.
• Appears to be multiple genetic defects
  (polygenic), modified by environmental factors.
• Deranged beta cell secretion of insulin
• Early disease has loss of the normal pulsatile
  and oscillating pattern of insulin
  secretion-insulin secretion is normal and plasma
  levels are normal
• Later disease has a mild to moderate deficiency
  of insulin which may be secondary to irreversible
  beta cell damage
• Insulin resistance
• Reduced responsiveness of peripheral tissues
  occurs in both obesity and pregnancy.
• Results in more persistent hyperglycemia with
  prolonged stimulation of the beta cell
• Suspected that reduced synthesis and
  translocation of GLUTs in muscle and fact cells
  underlies the insulin resistance

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Type 2 diabetes Associated factors

• Obesity
• 80 of type 2 patients Weight loss may reverse
  the symptoms.
• Chronic obesity leads to increased insulin
  resistance that can develop into diabetes, most
  likely because adipose tissue is a (recently
  identified) source of chemical signals (hormones
  and cytokines)
• Amylin
• Produced by the beta cells, copackaged and
  secreted with insulin accumulates in the
  sinusoidal space outside the beta cells may
  contribute to beta cell derangement.
• About 90-95 of all North American cases of
  diabetes are type 2, and about 20 of the
  population over the age of 65 has diabetes
  mellitus type 2
• There is also a strong inheritable genetic
  connection in type 2 diabetes having relatives
  (especially first degree) with type 2 is a
  considerable risk factor for developing type 2
  diabetes

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Type 2 diabetes Associated factors conts

• Genetic Defects of beta cell function
• A common amino-acid polymorphism (Pro12Ala) in
  peroxisome proliferator-activated receptor-
  (PPAR ) has been associated with type 2 diabetes.
  
• People homozygous for the Pro12 allele are more
  insulin resistant than those having one Ala12
  allele and have a 1.25-fold increased risk of
  developing diabetes. T
• There is also evidence for interaction between
  this polymorphism and fatty acids, thereby
  linking this locus with diet.

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Type 2 Diabetes mellitus risk factors

• Age, race and ethnicity, obesity, and lack of
  physical activity, diet, smoking, fat
  distribution.
• the genetics of type 2 diabetes is complex, and
  it is unlikely that single major genes will
  account for a substantial proportion of the
  disease.
• Despite numerous reports suggesting a substantial
  genetic contribution to the susceptibility of
  type 2 diabetes, no major susceptibility genes
  have been identified so far

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Type 2 diabetes Conts

• Some ethnic groups, such as most Native Americans
  and Hispanics, have a definite genetic
  susceptibility to diabetes, while some groups,
  including Caucasians, Melanesians, and Eskimos,
  are at low risk.
• Since Type II diabetes essentially did not exist
  100 years ago, it's obvious that a change in the
  environment has created the disease, but there is
  genetic susceptibility on top of that
• Genetic factors combine with environmental
  factors to cause diabetes diet and exercise can
  control diabetes. A group of Pima Indians in
  Mexico are believed to be genetically the same as
  the Pimas in Arizona, but live in area with no
  refrigeration, no trucks, no roads, no
  electricity, and no remote controlled
  televisions.
• The Mexican Pimas have no incidences of diabetes.

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Type 2 Env

• Major Susceptibility Locus for Type II Diabetes
• One locus on the distal part of the long arm of
  chromosome 2 in the human genome has been well
  characterized to be linked with type II diabetes
  in humans.  
• Hanis et al. (1996) performed a genome-wide
  search that revealed a major susceptibility locus
  for noninsulin dependent diabetes mellitus
  (125853) on chromosome 2.
• The study was performed on 330 affected sibpairs
  from Mexican American families living close to
  the Rio Grande River in Texas. Marker D2S125,
  which is located in the distal part of the long
  arm of chromosome 2, showed significant evidence
  of linkage to NIDDM and appeared to be a major
  factor affecting the development of diabetes
  mellitus in Mexican Americans. Hanis et al.
  (1996) proposed that the locus be designated
  NIDDM1."

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Case Study

• The prevalence of type 2 diabetes among
  Australian residents is 7.5 however, prevalence
  rates up to six times higher have been reported
  for indigenous Australian communities.
• Epidemiological evidence implicates genetic
  factors in the susceptibility of indigenous
  Australians to type 2 diabetes and supports the
  hypothesis of the "thrifty genotype," but, to
  date, the nature of the genetic predisposition is
  unknown.
• This study ascertained clinical details from a
  community of indigenous Australian descent in
  North Stradbroke Island, Queensland. In this
  population, the phenotype is characterized by
  severe insulin resistance.
• A genomewide scan was conducted, at an average
  resolution of 10 cM, for type 2 diabetes
  susceptibility genes in a large multigeneration
  pedigree from this community.
• Results
• Parametric linkage analysis undertaken using
  FASTLINK version 4.1p yielded a maximum two-point
  LOD score of 2.97 at marker D2S2345. Multipoint
  analysis yielded a peak LOD score of 3.9 lt1 cM
  from marker D2S2345, with an 18-cM 3-LOD support
  interval.
• Secondary peak LOD scores were noted on
  chromosome 3 (1.8 at recombination fraction
  0.05, at marker D3S1311) and chromosome 8 (1.77
  at 0.0, at marker D8S549). The study
  concluded that a region of significant positive
  linkage with type 2 diabetes exists on chromosome
  2q.

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Table 1Peak Two-Point LOD Scores for Chromosome
2q Markers
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