Diabetes Mellitus
Diabetes Mellitus- introduction
• DM- definition?
• DM-is not a single disease entity, composed of a group of
metabolic disorders sharing the common underlying feature of
hyperglycemia.
• Why hyperglycemia?
• results from defects in insulin secretion, insulin action, or, most
commonly, both.
• What’s the insulin?
• is a peptide hormone, produced by beta cells of the pancreas,
• What’s the function of Insulin?
• Play central role to regulating carbohydrate and fat metabolism in the
body. It causes cells in the liver, skeletal muscles, and fat tissue to
absorb glucose from the blood.
Diabetes Mellitus-epidemiology
• How common?
• DM- total number of people worldwide was estimated to be
between 151 million and 171 million .
• DM affects >20 million children& adults (USA).
• DM- affect= 7% of the population, (USA).
• DM- approximately 1.5 million new cases \ each year (USA).
• DM- the prevalence is increasingly sharply in the developing
world as people adopt more sedentary life styles.
• What’s the clinical importance in studying DM?
• The chronic hyperglycemia with attendant metabolic
dysregulation may be a\w secondary damage in multiple organ
systems, especially kidneys, eyes, nerves, blood vessels
• DM- is the leading cause of end-stage renal disease, adult-onset
blindness, and nontraumatic lower extremity amputations.
Diabetes Mellitus- diagnosis
• Blood glucose values (normal range)= usually (70 to 120 mg/dL)
• The diagnosis of diabetes: is established by classical signs and
symptoms with noting elevation of blood glucose by any one of
three criteria:
• 1. A random glucose concentration > 200 mg/dL,
• 2. A fasting glucose concentration > 126 mg/dL on more than one
occasion.
• 3. An abnormal oral glucose tolerance test (OGTT):
The glucose concentration > 200 mg/dL (2 hours after a standard
carbohydrate load)
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Examples of interpretation
Individuals with OGTT reading:
Fasting glucose <100 mg/dL, or < 140 mg/dL
Considered to be euglycemic.
Individuals with OGTT reading :
Fasting glucose > 100 mg/dL but < 126 mg/Dl
Considered to be impaired glucose tolerance, also
known as “pre-diabetes.”
• Individuals with OGTT values:
• Fasting glucose > 140 mg/dL but < 200 mg/dL.
• Considered to be impaired glucose tolerance, also
known as “pre-diabetes.”
Diabetes Mellitus- Classification
1. Type 1 diabetes mellitus.
2. Type II diabetes mellitus.
3. Genetic defect of Beta-cell function.
4. Genetic defects in insulin action.
5. Genetic syndrome associated with diabetes
6. Exocrine pancreatic defect
7. Endocrinopathies.
8. Infections.
9. Drugs.
10. Gestational diabetes
Diabetes Mellitus- Classification
Type 1 diabetes mellitus.(β-cell destruction, usually leading to absolute
insulin deficiency), Immune-mediated
2. Type II diabetes mellitus.(combination of insulin resistance and β-cell
dysfunction).
3. Genetic defect of Beta-cell function.(Maturity-onset diabetes of the young
(MODY), caused by mutations), Neonatal diabetes, Maternally inherited
diabetes and deafness, Insulin gene mutations,etc..
4. Genetic defects in insulin action.(Type-A-insulin resistance,Lipoatrophic
DM, including mutations in PPARG)
5. Genetic syndrome associated with diabetes.(Down’s, Turner, Kleinfelter
syndromes, etc,..)
6. Exocrine pancreatic defect(Chronic pancreatitis, tumour,etc)
7. Endocrinopathies(Acromegaly,Cushing,pheochromcytoma)
8. Infections.(CMV, Coxsackie B, Congenital rubella virus)
9. Drugs.(Glucocorticoids, Phenytoin, Thiazides, thyroid H.)
10. Gestational diabetes
1.
Diabetes Mellitus- Classification
1. Type 1 diabetes mellitus:
- Autoimmune disease, chr. By destruction of Beta
cells with absolute insulin deficiency.
- It account for 5-10% of all cases
- Mainly in younger patient age below< 20 year old.
2. Type II diabetes mellitus- caused by combination
- Peripheral resistance to insulin action
- Inadequate secretory response by the pancreatic β
cells (“relative insulin deficiency”).
- It account for 90-95% of all cases.
- Age: adult-onset, the prevalence increase in children &adolescents
- Risk groups: a\w with over-weight.
GLUCOSE HOMEOSTASIS:
three mechanisms
• 1) Glucose production in the liver.
• 2) Glucose uptake and utilization by peripheral
tissues, chiefly skeletal muscle.
• 3) Actions of insulin and counter-regulatory
hormones, including glucagon, on glucose uptake
and metabolism
INSULIN SYNTHESIS PATHWAY:
Outcome: Insulin+ C-peptide
Regulation of Insulin secretion (glucose, Intestinal
hormones, Amino acid certain)
• Intracellular transport of
glucose is mediated by
GLUT-2 (insulinindependent glucose
transporter in b cells).
• Glucose undergoes oxidative
metabolism in the b cell to yield
ATP.
• ATP inhibits an inward K+
channel receptor.
•
Inhibition of this receptor leads
to membrane depolarization,
influx of Ca2+ ions, and release
of stored insulin from b cells.
Metabolic actions of insulin in striated muscle,
adipose tissue, and liver.
Insulin action on a target cell
MAP kinase=mitogen-activated protein kinase pathway for
insulin &insulin-like growth factor (mitogenic=proliferation).
PI-3K= phosphatidylinositol-3-kinase (Metabolic activity)
PATHOGENESIS OF DM-TYPE 1
• DM-1 is an autoimmune disease in which islet
destruction is caused primarily by immune effector
cells (failure of self-tolerance in T-cells) reacting
against (TH1 “CK,TNF,INF” +CD8 “direct killer”)
endogenous β-cell antigens (insulin, GAD,
ICA512).
• DM-1 start in childhood become manifested in
puberty. Pathogenesis involve interplay:• 1) Genetic Susceptibility
• 2) Environmental Factors:
PATHOGENESIS OF DM-TYPE 1
1) Genetic Susceptibility
• Higher rate of diseases in Monozygotic vs dizygotic
twins- convincingly established a genetic basis for type 1
diabetes.
• Genome-wide association studies have identified
multiple genetic susceptibility loci for DM-1:• 1) The HLA locus contributes as much as 50% of the
genetic susceptibility to DM-1 (chr6p21,DR3\4).
• 2) Several non-HLA genes also confer susceptibility to
type 1 diabetes (CTLA4 and PTPN22 )
PATHOGENESIS OF DM-TYPE 1
• Environmental Factors:
• Infections- especially viral infections: (mumps, rubella,
coxsackie B, or cytomegalovirus) through three different
mechanism:
• 1) “bystander” damage: viral infections induce islet
injury and inflammation, leading to the release of
sequestered β-cell antigens and the activation of
autoreactive T cells.
• 2) (“molecular mimicry”):mimic β-cell antigens (X-Reaction)
• 3) Hypothesis (“predisposing virus”) early in life might
persist with subsequent re-infection with a related virus
(“precipitating virus”) that shares antigenic epitopes
leads to an immune response against infected islet cells.
Mechanisms of β-Cell Destruction
PATHOGENESIS OF TYPE 2 DM
• Much less in known–multifactorial complex
disease.
• 1) Environmental factors, such as a sedentary
life style and dietary habits.
• 2) Genetic factors are also involved:
• a) Concordance rate of 35% -60% in
monozygotic twins.
• B) Risk for type 2 diabetes in an offspring is
more than double if both parents are affected
• C) No HLA association or autoimmune reaction.
Pathogenesis of type 2
• Two major pathogenetic factors:
• 1- Insulin resistance: obesity plays an important
role by decreasing insulin receptors.
• 2-B cell dysfunction: inability of pancreas to
produce insulin to compensate for insulin resistance
(delayed or dysfunction).
• This may be due to deposition of amylin as amyloid
deposites the latter is cosecreted with insulin in high
amount due to insulin resistance. Amylin is toxic to
beta cells>>> will lead to B cell exhaustion& DM
PATHOGENESIS OF TYPE 2 DM
Obesity and Insulin Resistance.
• Insulin resistance: defined as the failure of target
tissues to respond normally to insulin, this lead:
• (a) Decreased uptake of glucose in muscle.
• (b) Reduced glycolysis and fatty acid oxidation in liver.
• (c) Inability to suppress hepatic gluconeogenesis.
• Obesity& distribution of fat has profound effects on
sensitivity of tissues to insulin. (Central> peripheral).
• The risk for diabetes increases as BMI increases
Obesity and Insulin Resistance.
• Obesity can adversely impact insulin sensitivity in ways:
• (1) Nonesterified fatty acids (NEFAs):
• (2) Adipokines.
• (3) Inflammation
• (4) Peroxisome proliferator-activated receptor γ
•
(PPAR γ)
Obesity and Insulin Resistance.
• (1) Nonesterified fatty acids (NEFAs):
*Inverse correlation b\w NEFATs & Insulin sensitivity .
• Excess circulating NEFAs are deposited in (liver,
muscles).
• Excess intracellular NEFAs overwhelm the fatty acid
oxidation pathways, leading to accumulation of
cytoplasmic intermediates like diacylglycerol (DAG) and
ceramide. which cause aberrant serine phosphorylation
of the insulin receptor and IRS proteins
• Excess NEFAs also compete with glucose for substrate
oxidation
Obesity and Insulin Resistance.
• (2) Adipokines:
• A variety of proteins secreted into the circulation by
adipose tissue, these are collectively termed adipokines
(or adipose cytokines). Examples:
• (a) Pro-hyperglycemic adipokines (e.g., resistin, retinol binding
protein 4 [RBP4])
• (b) Anti-hyperglycemic adipokines (leptin, adiponectin), Leptin
and adiponectin improve insulin sensitivity. by directly enhancing
the activity of the AMP-activated protein kinase (AMPK), an
enzyme that promotes fatty acid oxidation, in liver and skeletal
muscle.
• Notably, AMPK is also the target for metformin, a commonly
used oral antidiabetic medication.
• Adipose tissue is not merely a passive storage depot for
Obesity and Insulin Resistance.
• (3) Inflammation: Adipose tissue secretes a variety of
pro-inflammatory cytokines like, TNF, IL6.
• Reducing the levels of pro-inflammatory cytokines
enhances insulin sensitivity.
• (4) Peroxisome proliferator-activated receptor γ (PPAR
γ): a nuclear receptor and transcription factor expressed in
adipose tissue, plays a role in cell differentiation.
• Activation of PPARγ promotes secretion of anti-hyperglycemic
adipokines like adiponectin, and shifts the deposition of NEFAs
toward adipose tissue and away from liver and skeletal muscle.
• Mutations of PPARG – lead to monogenic diabetes.
• Thiazolidinediones “Antidiabetic drug”-acts as agonist ligands for
PPARγ and improves insulin sensitivity.
DM& Metabolic Derangements.
• Diabetic patient exhibit a wide spectrum of deranged
carbohydrate metabolism + derangement of
insulin function .
• Clinical features varying from those having mild
or asymptomatic disease to fully expressed clinical
disease .
• Two important acute metabolic complication of
diabetes mellitus are:
•
Diabetic Ketoacidosis.
Nonketotic hyperosmolar coma.
DM& Metabolic Derangements.
• Insulin is anabolic hormone .It is necessary
for:
1. Transmembrane transport of glucose and
amino acids.
2. Glycogen formation in the liver and in the
skeletal muscle.
3. Glucose conversion to triglicerides.
4. Nucleic acids synthesis.
5. Protein synthesis
DM& Diabetic Ketoacidosis (DKA).
 DKA- This complication occurs almost exclusively in DM-1
 1. DKA- Stimulated by severe insulin deficiency coupled
with absolute or relative increases of glucagon.
 2. The insulin deficiency causes excessive breakdown of
adipose stores, resulting in an increased levels of free fatty
acids (LIPOLYSIS) .
 3. Oxidation of such FFA acids within the liver through
acetyl-CoA produces ketone bodies,(KETOGENESIS)
 4. The rate at which ketone bodies are produced exceed the
rate at which can be utilized>>leading to ketonemia,and
ketonuria .
5. Hyperglycemia- increase gluconeogenesis (excess glucagon)
+ reduce glucose uptake (insulin deficiency)
DM& Non-ketotic hyperosmolar coma.
 This syndrome is caused by the severe
dehydratation resulting from sustained
hyperglycemic diuresis in patients who do not
drink enough water to compensate for urinary
losses.
Classification of DM
Istems
Type 1(IDDM)
Type2(NIDDM)
Age
children
adult
Insulin
decrease
Normal or increase
obesity
absent
present
Auto antibodies
ICA,IAA,GAD
Absent
Genetic,HLA
40%,HLADr3,4
80%,No HLA
association
Pathology
Insulinitis,lymphoid
infiltrate,beta cell atrophy
and fibrosis
No insulinitis,amyloid
deposites
ketoacidosis
common
Rare(Hyperosmolar
nonketotic)
THE END