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DM.pptx
1. Definition
• Diabetes mellitus (DM) refers to a group of
common metabolic disorders that share the
phenotype of hyperglycemia.
• Several distinct types of DM are caused by a
complex interaction of genetics and
environmental factors.
1
2. • Depending on the etiology of the DM, factors
contributing to hyperglycemia include:
Reduced insulin secretion
Decreased glucose utilization
Increased glucose production.
2
3. The worldwide prevalence of DM has risen
dramatically over the past two decades
• 30 million cases in 1985
• 285 million in 2010
• 522 million in 2030
3
Epidemiology
IDF Diabetes Atlas: Global estimate of the prevalence of diabetes for 2011 and 2030, 94(2011) 311-321
4. Diabetes Prevalence by Age and Sex
(no difference)
The IDF Diabetes Atlas 5th Edition, 2011
4
5. Population: 70,049,262 (Dec 2006)
Total area: 1.648 million km2
• about 7% people had diabetes in
2008 & expected to reach 8.4% in
2025
• About 16.8% people had IGT
• For 2007, the estimates was that
(14.9% of all female deaths) and
(7.5% of all male deaths) could be
attributed to DM
DF; Diabetes Atlas 3rd edition; 2007
Diabetes care 31:96-98; 2008
PLoS ONE 6(10: e 26725)
Diabetes prevalence in Iran
6. Classification of Diabetes Mellitus
I. Type 1 diabetes (beta cell destruction, usually leading to
absolute insulin deficiency)
II. Type 2 diabetes (may range from predominantly insulin
resistance with relative insulin deficiency to a
predominantly insulin secretary defect with insulin
resistance)
III. Gestational diabetes mellitus (GDM)
IV. Other specific types of diabetes
Source: Adapted from American Diabetes Association, 2013
7. Other Specific Type
• Genetic defects of ß-cell function
• Genetic defects in insulin action
• Diseases of the exocrine pancreas
• Endocrinopathies
• Drug- or chemical-induced
• Physiologic stress (e.g. infection)
• Uncommon forms of immune-mediated diabetes
• Other genetic syndromes sometimes associated
with diabetes
ADA; DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012 7
9. Criteria for the diagnosis of diabetes
• 1. A1C 6.5%. The test should be performed in a laboratory using a
method that is NGSP certified and standardized to the DCCT assay.*
OR
• 2. FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for
at least 8 h.*
OR
• 3. 2-h plasma glucose 200 mg/dl (11.1 mmol/l) during an OGTT. The test
should be performed as described by the WHO, using a glucose load
containing the equivalent of 75 g anhydrous glucose dissolved in water.*
OR
• 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic
crisis, a random plasma glucose 200 mg/dl (11.1 mmol/l)
*In the absence of unequivocal hyperglycemia, criteria 1–3 should be
confirmed by repeat testing.
9
10. IFG = FPG 100–125 mg/dl (5.6–6.9 mmol/l)
IGT = 2-h plasma glucose 140 mg/dl (7.8
mmol/l) to 199 mg/dl (11.0 mmol/l)
Categories of increased risk for diabetes
10
A1C =5.7–6.4%
ADA; DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2013
11. Biosynthesis
• Insulin is produced in the beta cells of the pancreatic islets
• Initially synthesized as single-chain 86-amino-acid precursor
polypeptide, pre-pro-insulin
• Proteolytic processing removes amino-terminal signal peptide,
giving rise to pro-insulin
• Pro-insulin is structurally related to IGF I and II, which bind
weakly to insulin receptor
• Cleavage of an internal 31-residue fragment from pro-insulin
generates the C peptide and the A (21 amino acids) and B (30
amino acids) chains of insulin, which are connected by
disulfide bonds
11
12. …Continued
• The mature insulin molecule and C peptide are stored
together and cosecreted from secretory granules in the
beta cells
• C peptide is cleared more slowly than insulin
⇒ useful marker of insulin secretion in the evaluation
of hypoglycemia
12
13. • β cells cosecrete islet amyloid polypeptide
(IAPP) or amylin, a 37-amino-acidpeptide,
along with insulin.
• The role of IAPP in normal physiology is
unclear, but it is the major component of
amyloid fibrils found in the islets of patients
with type 2 diabetes
• An analogue is sometimes used in treating
both type 1 and type 2 DM
13
…Continued
14. Secretion
• Glucose is the key regulator of insulin secretion
• BS >70 mg/dL stimulate insulin synthesis
• Glucose stimulation of insulin secretion begins
with its transport into the βcell by the GLUT2
glucose transporter
• Glucose phosphorylation by glucokinase is the
rate-limiting step that controls glucose-
regulated insulin secretion.
14
15. • Pyruvate: The metabolism of glucose-6-phosphate via
glycolysis generates ATP, which inhibits the activity of
an ATP-sensitive K+ channel
• Inhibition of this K+ channel induces β cell membrane
depolarization, → influx of calcium and stimulates
insulin secretion
16. …continued
• Insulin secretory profiles reveal a pulsatile pattern
→secretory bursts occurring about every 10 min,
superimposed upon greater amplitude oscillations of
about 80 to 150 min
• Meals or other major stimuli of insulin secretion induce
large (four-to fivefold increase versus baseline) bursts
of insulin secretion that usually last for 2 to 3 h before
returning to baseline
• Derangements in these normal secretory patterns are
one of the earliest signs of β cell dysfunction in DM
16
17. • Are released from neuro-endocrine cells of GI tract
• Following food ingeston
• Amplify glucose-stimulated insulin secretion and
suppress glucagon secretion
• Glucagon-like peptide 1 (GLP-1):
The most potent incretin, is released from L cells in
the small intestine → stimulates insulin secretion
when the blood glucose is above the fasting level
17
Incretins
18. Insulin Action
• Once insulin is secreted into the portal venous system,
~50% is degraded by the liver
• Unextracted insulin enters the systemic circulation where
it binds to receptors in target sites
• Binding to its receptor stimulates intrinsic tyrosine kinase
activity, leading to receptor autophosphorylation and the
recruitment of intracellular signaling molecules, such as
insulin receptor substrates (IRS)
18
19. • These proteins initiate a complex cascade of
phosphorylation and dephosphorylation reactions, →
metabolic and mitogenic effects of insulin
• Activation of phosphatidylinositol-3′-kinase (PI-3-kinase)
→ translocation of glucose transporters ( GLUT4) to the
cell surface → glucose uptake by skeletal muscle and fat
• Activation of other insulin receptor signaling pathways
induces glycogen synthesis, protein synthesis, lipogenesis
19
20. Type 1 DM
Type 1 DM is the result of interactions of
• genetic
• Environmental
• Immunologic factors
that ultimately lead to the destruction of the
pancreatic β cells and insulin deficiency.
20
21. • Individuals with a genetic susceptibility have normal β
cell mass at birth but begin to lose secondary to
autoimmune destruction that occurs over months to
years
• Autoimmune process may be triggered by an infectious
or environmental stimulus and to be sustained by a β
cell–specific molecule
• In the majority of individuals, immunologic markers
appear after the triggering event but before diabetes
becomes clinically overt
• Β cell mass begins to decline ⇨ insulin secretion
becomes progressively impaired 21
…continued
22. • Rate of decline in β cell mass varies widely
among individuals,
• Some patients progressing rapidly to clinical
diabetes & others evolving more slowly
• Features of DM do not become evident until
majority of β cells are destroyed (70-80%)
22
…continued
23. 23
Temporal model for development of type 1 diabetes
Adapted from Medical Management of Type 1 Diabetes, 3rd ed, JS Skyler (ed). American Diabetes Association,
Alexandria, VA, 1998
24. • “Honeymoon” phase:
• After the initial clinical presentation of T1DM,
glycemic control is achieved with modest doses
of insulin or, rarely, insulin is not needed
• As the autoimmune process ⇨destroys the
remaining β cells, this phase disappears & the
individual becomes completely insulin deficient
24
…continued
25. • Although other islet cell types
Alpha cells (glucagon-producing)
Delta cells (somatostatin-producing),
PP cells (pancreatic polypeptide-producing)
They are inexplicably spared from the autoimmune
process
25
…continued
26. Genetic Considerations
• Genetic susceptibility to T1DM involves multiple genes
• Concordance of T1DM in identical twins ranges
between 40-60%,
• Additional modifying factors must be involved in
determining whether diabetes develops
• The major susceptibility gene for T1DM is located
in the HLA region on chromosome 6
26
27. … Continued
• Most individuals with T1DM have the HLA DR3
and/or DR4 haplotype
• Nevertheless, most individuals with predisposing
haplotypes do not develop diabetes
• The risk of developing T1DM is increased ten fold in
relatives of individuals with the disease
• Most individuals with T1DM do not have a first-
degree relative with this disorder
27
28. Pathophysiology
• Pancreatic islets are infiltrated with lymphocytes (insulitis)
• Abnormalities in the humoral and cellular arms of the immune
system:
Islet cell auto antibodies
Activated lymphocytes in the islets, peripancreatic lymph
nodes, and systemic circulation
T lymphocytes that proliferate when stimulated with islet
Release of cytokines within the insulitis
• β cells seem to be particularly susceptible to the toxic effect of
some cytokines [TNF and IL-1]
28
29. • The precise mechanisms of β cell death are not known
• May involve formation of nitric oxide metabolites,
apoptosis, and direct CD8+ T cell cytotoxicity
• Suppression of the autoimmune process (cyclosporine, T
lymphocyte antibodies) at the time of diagnosis of
diabetes ⇨↓beta cell destruction,
• The safety of such interventions is unknown
29
… Continued
30. Immunologic Markers
• Islet cell autoantibodies (ICAs)
A composite of several different antibodies directed at pancreatic
islet molecules such as GAD, insulin… and serve as a marker of the
autoimmune process of T1DM
• Testing for ICAs can be useful
Classifying type of DM
Identifying non-diabetic individuals at risk for developing
T1DM
30
31. • ICAs ( islet cell Ab) are present in >85% diagnosed with new-
onset T1DM
• 5-10% of individuals with newly diagnosed T2DM and
occasionally in individuals with GDM (<5%)
• ICAs are present in 3-4% of first-degree relatives of individuals
with T1DM
• In combination with impaired insulin secretion after IV-GTT,
predict a >50% risk of developing T1DM within 5 years.
• Measurement of ICAs in nondiabetic individuals is a research tool
31
… Continued
32. Prevention of Type 1 DM
In patients with new-onset type 1 DM,
treatment with anti-CD3 monoclonal antibodies, a GAD
vaccine , Anti-B lymphocyte monoclonal antibody
have been shown to slow the decline in C-peptide
levels.
32
34. Type 2 DM
• Insulin resistance and abnormal insulin
secretion are central to the development of
type 2 DM.
• Although the primary defect is controversial,
most studies support the view that insulin
resistance precedes an insulin secretory
defect but that diabetes develops only when
insulin secretion becomes inadequate.
34
35. Genetic Considerations
• T2DM has a strong genetic component
• Polygenic and multifactorial
• Concordance of T2DM in identical twins is between 70
- 90%
• If both parents have T2DM, the risk approaches 40%
35
36. • The genes that predispose to T2DM are incompletely
identified
• Most prominent is a variant of the transcription factor
7-like 2 gene that has been associated with T2DM and
IGT
• Genetic polymorphisms have also been found
• These genetic alterations increase the susceptibility
T2DM and predict to alter insulin secretion.
36
… Continued
37. • Impaired insulin secretion
• Insulin resistance
• Excessive hepatic glucose production
• Abnormal fat metabolism
• In the early stages:
• Glucose tolerance remains near-NL, despite insulin
resistance,
• Pancreatic β cells compensate by ↑insulin output
37
Pathophysiology of T2DM
38. … Continued
• As insulin resistance and compensatory
hyperinsulinemia progress,
• Pancreatic islets are unable to sustain the
hyperinsulinemic state
39. Pathophysiology of T2DM
• IGT:
• characterized by elevations in postprandial
glucose
• IFG or Fasting hyperglycemia:
• ⇩insulin secretion and ⇧ hepatic glucose
production ⇨overt DM
• Ultimately, β cell failure may ensue
40. Metabolic Abnormalities
Associated with T2DM
1- Abnormal Muscle and Fat Metabolism
2- Impaired Insulin Secretion
3- Increased Hepatic Glucose and Lipid Production
40
41. Abnormal Muscle and Fat Metabolism
• Insulin resistance is a prominent feature of T2DM
• Insulin resistance ⇨↓ glucose utilization by insulin-
sensitive tissues and ↑ hepatic glucose output
• ↑ Hepatic glucose output predominantly accounts for
↑ FPG
• ↓ Peripheral glucose usage ⇨ postprandial
hyperglycemia
41
42. • The precise molecular mechanism leading to insulin
resistance has not been known
• ⇩Insulin receptor levels and tyrosine kinase activity in
skeletal muscle, but these alterations are most likely
secondary to hyperinsulinemia and are not a primary
defect
• Therefore, "post-receptor" defects may play the
predominant role in insulin resistance
42
Abnormal Muscle and Fat Metabolism
43. • Impaired fatty acid oxidation and lipid accumulation
within skeletal myocytes may generate reactive
oxygen species such as lipid peroxides
• Accumulation of lipid within skeletal myocytes
Impair mitochondrial oxidative phosphorylation
↓ insulin-stimulated mitochondrial ATP production
43
Abnormal Muscle and Fat Metabolism
44. Abnormal Muscle and Fat Metabolism
• Not all insulin signal transduction pathways are
resistant to the effects of insulin (e.g., those
controlling cell growth)
• Hyperinsulinemia
• Increase the insulin action through these
pathways,
• Accelerating diabetes-related conditions such as
atherosclerosis
45. • The obesity accompanying T2DM, thought to be part of
the pathogenic process
• ↑Adipocyte mass leads to ↑circulating FFA and other
fat cell products (nonesterified free fatty acids, leptin,
TNF-α, and adiponectin…)
45
… Continued
46. • FFA
• Impair glucose utilization in skeletal muscle
promote glucose production by the liver
Impair β cell function
• Adiponectin
• An insulin-sensitizing peptide, ↓in obesity →may
↑ hepatic insulin resistance
• ⇩ Adiponectin ⇨inflammatory state and may
explain ↑ markers of inflammation such as IL-6
and CRP in type 2 DM
47. Impaired Insulin Secretion
• The reason(s) for the decline in insulin secretory
capacity in type 2 DM is unclear
• A second genetic defect—superimposed upon insulin
resistance - leads to β cell failure
• β cell mass is decreased in individuals with long-
standing type 2 diabetes
• Metabolic environment of diabetes may also
negatively impact islet function (glucose toxicity and
lipotoxicity)
47
48. Increased Hepatic Glucose and Lipid Production
• ↑ Hepatic glucose production
• Occurs early in the course of DM,
• After the onset of insulin secretory abnormalities and
insulin resistance in skeletal muscle
• Insulin resistance in adipose tissue and obesity⇨ ↑FFA
flux from adipocytes, ⇨ ↑ VLDL and TG synthesis in
hepatocytes
48
49. • This lipid storage or steatosis in the liver may
lead to nonalcoholic fatty liver disease (NASH)
and abnormal liver function tests
• This is also responsible for the dyslipidemia
found in type 2 DM (↑ TG, ↓ HDL, ↑small
dense LDL)
50. Insulin Resistance Syndromes
Metabolic Syndrome
• Hypertension: SBP>130 mm Hg o r
• DBP >85 mm Hg
• Dyslipidemia: TG>150 mg/dL, HDL<40 mg/dL for
men and < 50 mg/dL for women，
• Central or visceral obesity: waist circumference
> 102 cm (M) >88 cm (F)
• DMT2 or IGT/IFG
Accelerated cardiovascular disease.
50
55. Diet Control
• Individuals who have pre-diabetes or diabetes
should receive individualized diet as needed to
achieve treatment goals
• Either the patient is taking insulin or oral therapy
• Over weight should be reduced
• The diet for a diabetic patient is not so different
from the healthy diets for the whole population
55
57. DKA&HHS
• DKA Was formerly considered a hallmark of DMT1
• Occurs also in individuals who lack immunologic features
of type 1 DM
• Obese individuals with type 2 DM
• HHS is primarily seen in type 2 DM.
• Both disorders
• absolute or relative insulin deficiency
• volume depletion
• acid base abnormalities.
• exist aIong a continuum of hyperglycemia with or w/o
ketosis.
58. Precipitating causes
• Infection: Even in the absence of fever.
• Tissue ischemia : MI & CVA
• Omission of insulin :
• Because of an eating disorder，
• Mental health disorders，
• An unstable psychosocial environment
59. Pathophysiology of DKA
• DKA results from relative or absolute insulin deficiency
combined with counter regulatory hormone excess
(glucagon, catecholamines, cortisol, GH) .
• Both insulin deficiency and glucagon excess, are necessary
• ↑Glucagon ⇨↓activity of pyruvate kinase,
• ↓insulin⇨ ↑activity of phosphoenolpyruvate carboxy
kinase
• These changes shift the handling of pyruvate toward
glucose synthesis and away from glycolysis 59
60. … Continued
• ↑glucagon and catecholamines in the face of
↓insulin levels promote glycogenolysis
• Insulin deficiency → ↓GLUT4 glucose
transporter→ impairs glucose uptake into
skeletal muscle and fat → ⇩ intracellular
glucose metabolism
60
61. … Continued
• ↓ insulin levels, with ↑catecholamines, glucagon
and GH: ⇧ lipolysis and release of FFA
• Normally, FFA are converted to TG or VLDL in the liver
• ⇧Glucagon⇨ alters hepatic metabolism to ketone
body formation, through activation of enzyme
carnitine palmitoyl transferase I
• This enzyme is crucial for fatty acid transport
into mitochondria⇨ conversion to ketone bodies
61
62. … Continued
• At physiologic pH, ketone bodies exist as ketoacids, which
are neutralized by bicarbonate
• As bicarbonate stores are depleted, metabolic acidosis
ensues
• ↑lactic acid production also contributes to acidosis
• ↑FFA ⇨↑ TG and VLDL.
• ↓VLDL clearance : because of↓ the activity of insulin-
sensitive LPL in muscle and fat
• Hyper-TG :may be severe enough to cause pancreatitis
62
66. Laboratory Abnormalities In DKA
• Hyperglycemia: BS>250
• Ketosis: Ketonemia is a consistent finding in DKA
and distinguishes it from simple hyperglycemia.
• Metabolic acidosis: Serum HCO3<15 (↑ anion gap)
• The degree of acidosis and hyperglycemia do not
necessarily correlate closely
67. … Continued
• Despite a total-body K deficit, mildly↑serum K at
presentation secondary to the acidosis.
• ↓Total-body stores of Na, Cl, phosphorus, Mg
• ↓ Serum Na due to hyperglycemia (1.6-meq)↓serum
Na for each 100-mg/dL↑ BS .
• NL serum Na in the setting of DKA indicates a more
profound water deficit.
68. … Continued
• Calculated serum osmolality
(2 x [serum Na + serum K] + plasma glucose
[mg/dL] /1 8 + BUN/2.8) is mildly to
moderately elevated，
To a lesser degree than that found in HHS
69. … Continued
• ↑BUN and Cr:
Reflect intravascular volume depletion.
Interference from acetoacetate → falsely ↑serum Cr
• Leukocytosis, hypertriglyceridemia,
hyperlipoproteinemia
• Hyperamylasemia: amylase is usually of salivary
origin, not diagnostic of pancreatitis.
Serum Iipase should be obtained if pancreatitis is
suspected.
72. • History
• The typical patient is an elderly with DMT2
• Debilitating condition (prior stroke or dementia)
• several-week history of polyuria, weight loss and
↓oral intake
• ⇨Mental confusion, lethargy or coma.
• Symptoms of nausea, vomiting, and abdominal
pain are absent
73. • PH/EX:
• Profound dehydration
• Hypotension，
• Tachycardia，
• Altered mental status
• Absence of kussmaul respirations
74. Pathophysiology of HHS
• Relative insulin deficiency and inadequate fluid
intake are the underlying causes.
• ↓ Insulin ⇨
• ↑Hepatic glucose production (through glycogenolysis
and gluconeogenesis)
• Impairs glucose utilization in skeletal muscle
• Hyperglycemia ⇨
• Induces an osmotic diuresis ⇨ ↓intravascular volume,
exacerbated by inadequate fluid replacement.
75. • The absence of ketosis : Not understood.
• The insulin deficiency is only relative and less
severe than in DKA.
• Lower levels of counter regulatory hormones and
• free fatty acids
• liver is less capable of ketone body synthesis
• The insulin/glucagon ratio does not favor
ketogenesis.
76. • Marked hyperglycemia: (BS may be > 1000 mg/dL
• Hyperosmolality ( >350 mosmol/L)，
• Pre renal azotemia.
• The measured serum Na may be NL or slightly↓
despite the marked hyperglycemia.
• ↑Corrected serum Na
• Acidosis and ketonemia are absent or mild.
• A small anion-gap metabolic acidosis secondary to
↑ lactic acid.
• Moderate ketonuria due to starvation
82. The Diabetes Control and Complications Trial
(DCCT)
– Multicenter, randomized study of T1DM
– To assess effect of intensive glycemic control
vs. conventional therapy on:
• development and progression of retinopathy and other
long-term complications
DCCT Research Group. N Engl J Med. 1993;329:977-986
82
83. Features Of Diabetes-Related
Complications
(1) Duration and degree of hyperglycemia correlate with
complications.
(2) Intensive glycemic control is beneficial in all forms of
DM.
(3) Blood pressure control is critical, especially in type 2
DM.
(4) Survival in patients with type 1 DM is improving, and
diabetes-related complications are declining.
(5) Not all individuals with diabetes develop diabetes-
related complications, suggesting a genetic susceptibility
for developing particular complications.
84. Mechanisms of Complications
• Four theories explain how hyperglycemia might lead
to the chronic complications of DM.
• First: increased intracellular glucose leads to the
formation of advanced glycosylation end products
(AGEs) via the nonenzymatic glycosylation of intra-
and extracellular proteins.
• AGEs accelerate atherosclerosis, promote glomerular
dysfunction, reduce nitric oxide synthesis, induce
endothelial dysfunction, and alter extracellular
matrix composition and structure.
85. • second : hyperglycemia increases glucose
metabolism via the sorbitol pathway.
• Intracellular glucose is predominantly metabolized by
phosphorylation and subsequent glycolysis, but
when increased, some glucose is converted to
sorbitol by the enzyme aldose reductase.
• Increased sorbitol alters increases cellular osmolality,
generates reactive oxygen species, and other types
of cellular dysfunction.
86. • third : hyperglycemia increases the formation of
diacylglycerol leading to activation of protein kinase
C (PKC).
• Among other actions, PKC alters the transcription of
genes for fibronectin, type IV collagen, contractile
proteins, and extracellular matrix proteins in
endothelial cells and neurons.
87. • fourth : hyperglycemia increases the flux through
the hexosamine pathway, which generates fructose-
6-phosphate, a substrate for O-linked glycosylation
and proteoglycan productionchanges in gene
expression of transforming growth factor
• Growth factors appear to play an important role in
DM-related complications, Vascular endothelial
growth factor A (VEGF-A) is increased locally in
diabetic proliferative retinopathy and decreases
after laser photocoagulation.
88. Glycemic Control and Complications
• The Diabetes Control and Complications Trial (DCCT)
provided definitive proof that reduction in chronic
hyperglycemia can prevent many of the early
complications of 1 DM.
• reduced nonproliferative and proliferative
retinopathy (47%), microalbuminuria (39%), clinical
nephropathy (54%), neuropathy (60%).
• gain 7.7 additional years of vision, 5.8 additional
years free from ESRD, and 5.6 years free from lower
extremity amputations.
89. • DM is the leading cause of blindness between the ages
of 20 and 74 in the US
• individuals with DM are 25 times more likely to
become legally blind than individuals without DM
• Blindness is primarily the result of progressive diabetic
retinopathy and clinically significant macular edema
89
Retinopathy & Blindness in DM
90. Major Risk Factors for the Development of
Diabetic Retinopathy
• ↑ duration of DM
• Type of DM (type1>type2)
• Genetic susptibility
• Hypertension
• Hypercholestrolemia
• Diabetic control
• Presence of micro/macroalbuminuria
• Smoking
• Pregnancy
• Anemia 90
91. Pathophysiologic Mechanisms Invoked In
Nonproliferative Retinopathy
• Loss of retinal pericytes
• ↑retinal vascular permeability
• Alterations in retinal blood flow
• Abnormal retinal microvasculature
all of which lead to retinal ischemia
91
92. Proliferative Diabetic Retinopathy
• The appearance of neovascularization in response to
retinal hypoxia is the hallmark
• These newly formed vessels appear near the optic
nerve and/or macula and rupture easily, leading to
vitreous hemorrhage, fibrosis, and ultimately retinal
detachment
• Not all individuals with NPDR develop PDR, but the
more severe the nonproliferative disease, the greater
the chance of evolution to PDR within 5 years
92
93. • NPDR is found in almost all individuals who have had
DM for >20 years (25% incidence with 5 years, and 80%
incidence with 15 years of type 1 DM)
• Clinically significant macular edema can occur when only
NPDR is present
• Fluorescein angiography is useful to detect macular edema,
which is associated with a 25% chance of moderate visual
loss over the next 3 years
93
94. • Diabetic nephropathy is the leading cause of ESRD
and DM-related morbidity and mortality.
• Both microalbuminuria and macroalbuminuria in
individuals with DM ⇨ ↑risk of cardiovascular
disease.
• Individuals with diabetic nephropathy commonly
have diabetic retinopathy.
94
Diabetic Nephropathy
95. Pathogenesis Of Diabetic Nephropathy
The mechanisms by which chronic hyperglycemia leads to
ESRD, incompletely defined:
• The effects of soluble factors :(growth factors,
angiotensin II, endothelin,..)
• Hemodynamic alterations in the renal microcirculation
(glomerular hyperfiltration or hyperperfusion,
↑glomerular capillary pressure)
• Structural changes in the glomerulus
(↑extracellular matrix, basement membrane thickening,
mesangial expansion, fibrosis)
• Smoking accelerates ↓ renal function
95
96. Continue…
• Because only 20–40% of patients with diabetes
develop diabetic nephropathy, additional
susceptibility factors remain unidentified.
• One known risk factor is a family history of diabetic
nephropathy.
96
97. Natural History Of Diabetic Nephropathy
• Glomerular hyperperfusion and renal hypertrophy
occur in the first years after the onset of DM and
cause ↑ (GFR)
• During the first 5 years of DM, thickening of
glomerular basement membrane, glomerular
hypertrophy, and mesangial volume expansion occur
as GFR returns to normal
• After 5 to 10 years of type 1 DM, ~40% of individuals
begin to excrete small amounts of albumin in the
urine
97
98. Time course of development of diabetic
nephropathy
98
Harrison’s principles of internal medicine.2012
99. Microalbuminuria
• 30 to 300 mg/d in a 24-h collection or 30 to 300
µg/mg creatinine in a spot collection (preferred
method)
• The early pathologic changes and albumin excretion
abnormalities are reversible with normalization of
plasma glucose
99
100. macroalbuminuria
• The appearance of microalbuminuria in T1DM is an
important predictor of progression to
macroalbuminuria(>300 mg/d) or overt nephropathy
• Once overt proteinuria is present, there is a steady
decline in GFR, and ~50% of individuals reach ESRD in
7 -10 yrs
• Once overt nephropathy develops, the pathologic
changes are likely irreversible
102. Nephropathy in type 2 DM
(1) Microalbuminuria or overt nephropathy may be
present at diagnosis,
(2) HTN more commonly accompanies microalbuminuria
or overt nephropathy
(3) Microalbuminuria may be less predictive of diabetic
nephropathy
(4) Albuminuria in DM may be secondary to factors
unrelated to DM,
such as HTN, CHF, prostate disease, or infection
102
104. The accompaniments to diabetic
nephropathy
• Hypertension
• Macrovascular Disease
• Severe Retinopathy
• Neuropathy
• Hyperlipidemia
104
105. The optimal therapy for diabetic nephropathy is
prevention by control of glycemia .
Other effective Interventions
(1) improved glycemic control,
(2) strict blood pressure control,
(3) administration of an ACE inhibitor or ARB.
(4) Treatment of dyslipidemia.
107. • Diabetic neuropathy occurs in approximately
50% of individuals with long-standing type 1
and type 2 DM
• Both myelinated and unmyelinated nerve
fibers are lost
107
108. Diabetic Neuropathy
– Slowly progressive disease preferentially affecting
the long axons
– 30- 40% of all diabetics are symptomatic
• 60% have neuropathy (symptomatic or asymptomatic)
– Peripheral symptoms:
• numbness/tingling in the feet, cramps, sensitivity/
insensitivity to touch, loss of balance/coordination
– Autonomic symptoms:
• urinary incontinence, loss of sexual response, gastric stasis,
orthostatic hypotension
– Exact etiology unknown
Diabetic Neuropathy. July 1995 (updated 1996). NIDDK publication NIH 93-3185.
Vinik AI et al. In: Diabetes Mellitus. 1996:737-751. 108
109. Distal Symmetric Poly-neuropathy
•The most common form of
diabetic neuropathy
•Symptoms include a sensation of
numbness, tingling, sharpness, or
burning that begins in the feet and
spreads proximally
•Pain typically involves the lower
extremities, is usually present at
rest, and worsens at night
•P/E reveals sensory loss, loss of
ankle reflexes, and abnormal
position sense
109
110. 110
• As diabetic neuropathy progresses, the
pain subsides and eventually disappears,
but a sensory deficit in the lower extremities
persists
• Both an acute (lasting <12 m) and a chronic
form of painful diabetic neuropathy have
been described
111. Diabetic Radiculopathy
• Severe disabling pain in the distribution of one or more
nerve roots
• It may be accompanied by motor weakness
• Intercostal or truncal radiculopathy causes pain over the
thorax or abdomen
• Involvement of the lumbar plexus or femoral nerve may
cause pain in the thigh or hip and may be associated with
muscle weakness in the hip flexors or extensors (diabetic
amyotrophy)
• Fortunately, usually self-limited and resolve over 6 to 12
months
111
112. Mononeuropathy
• Dysfunction of isolated cranial or peripheral nerves
• Pain and motor weakness in the distribution of a
single nerve
• Vascular etiology has been suggested, but the
pathogenesis is unknown
• Peripheral mononeuropathies or simultaneous
involvement of more than one nerve
(mononeuropathy multiplex) may also occur
112
113. Mononeuropathy
• Involvement of the third cranial nerve is most
common and is heralded by diplopia.
• Physical examination :
• ptosis and opthalmoplegia with normal pupillary
constriction to light,
• usually self-limited
• Sometimes cranial nerves IV, VI, or VII (Bell's palsy)
are affected
114. Autonomic Neuropathy
• Involving the cholinergic, noradrenergic, and
peptidergic (pancreatic polypeptide, substance P)
systems
• Autonomic neuropathies affecting the cardiovascular
system cause a resting tachycardia and orthostatic
hypotension
• Gastroparesis and bladder-emptying abnormalities
114
115. Autonomic Neuropathy
• Sympathetic nervous system dysfunction:
• Hyperhidrosis of the upper extremities and
anhidrosis of the lower extremities
• May reduce counter regulatory hormone release,
leading to an inability to sense hypoglycemia
appropriately (hypoglycemia unawareness)
116. 116
Features of Autonomic Neuropathy
Postural hypotension
Resting tachycardia suggesting cardiac denervation
Diarrhea or Gastroparesis
Bladder dysfunction/Urinary retention
Gustatory sweating
During anesthesia-can be associated with respiratory arrest
and/or cardiac arrythmia (rare)
Erectile dysfunction-
117. GASTROINTESTINAL/GENITOURINARY
DYSFUNCTION
▪ Occurs in long-standing type 1 and 2 DM
▪ The most prominent GI symptoms
▪ Gastroparesis: delayed gastric emptying)
▪ present with : anorexia, nausea, vomiting, early satiety, and
abdominal bloating.
▪ Constipation or diarrhea: altered small- and large-bowel
motility Gastroparesis
▪ Microvascular complications (retinopathy and neuropathy)
are usually present.
118. ▪ n type 1 DM, these symptoms should also prompt
evaluation for celiac sprue because of its
increased frequency.
119. GASTROINTESTINAL DYSFUNCTION
▪ Female sexual dysfunction :
▪ Reduced sexual desire, dyspareunia, reduced vaginal
lubrication
▪ Diabetic cystopathy:
▪ Inability to sense a full bladder and a failure to void
completely.
▪ Diagnostic evaluation includes cystometry and
urodynamic studies.
120. GASTROINTESTINAL DYSFUNCTION
▪ Male sexual dysfunction :
▪ Erectile dysfunction and retrograde ejaculation
▪ One of the earliest signs of diabetic neuropathy .
121. Heart Disease and Stroke in
Diabetes Patients
The Framingham Heart Study revealed a
marked increase in PAD, CHF, CHD, MI,
and sudden death (risk increase from one-
to fivefold) in DM.
• prognosis for individuals with diabetes who
have coronary artery disease or MI is worse
than for nondiabetics.
• C .
121
122. • CHD is more likely to involve multiple vessels
• ↑Cerebrovascular disease in DM (threefold increase
in stroke).
• After controlling for all known cardiovascular risk
factors，
• Type 2 DM increases the cardiovascular death
twofold in men and fourfold in women.
123. • Type 2 DM patients without a prior MI have a
similar risk for coronary artery-related events
as nondiabetic individuals who have had a
prior MI
• Cardiovascular risk is lower and not equivalent in a
younger individual with a brief duration of type 2 DM
125. HbA1c <7.0%
3.5-yr
Incidence
(%)
Duration of Diabetes (yr)
HbA1c ≥7.0%
<6 ≥6
0
5
10
15
20
25
Kuusisto J et al. Diabetes. 1994;43:960-967.
Relationship between glycemic control and coronary heart
disease events in T2DM patients (ages 65 to 74)
125
126. • Hypertension Hypertension can accelerate other complications of
DM, particularly CVD, nephropathy, and retinopathy.
• In targeting a goal of blood pressure of <140/80 mmHg, therapy
should first emphasize lifestyle modifications such as weight loss,
exercise, stress management, and sodium restriction. The BP goal
should be individualized.
• In some younger individuals, the provider may target a blood
pressure of <130/80 mmHg. Realizing that more than one agent is
usually required to reach the blood pressure goal, the ADA
recommends that all patients with diabetes and hypertension be
treated with an ACE inhibitor or an ARB.
3. HTN management
127. Recommendations:
Glycemic, Blood Pressure, Lipid Control in Adults
A1C <7.0%*
Blood pressure <140/80 mmHg†
Lipids: LDL
cholesterol
<100 mg/dL (<2.6 mmol/L)‡
Statin therapy for those with history
of MI or age >40+ or other risk
factors
129. ▪ DM is the leading cause of nontraumatic lower extremity amputation
in the United States.
▪ The reasons for the increased incidence of these disorders in DM
involve the interaction of several pathogenic factors: neuropathy,
abnormal foot biomechanics, PAD, and poor wound healing.
130. • Motor and sensory neuropathy lead to
abnormal foot muscle mechanics and to
structural changes in the foot (hammer toe,
claw toe deformity, prominent metatarsal
heads, Charcot joint).
• Autonomic neuropathy results in anhidrosis
and altered superficial blood flow in the foot,
which promote drying of the skin and fissure
formation.
131. Risk Factors for Diabetic Foot
• Duration of DM > 10 years
• Male
• Abnormal structure of foot (bony abnormalities, callus,
thickened nails)
• PAD
• History of previous ulcer or amputation,
• visual impairment, and poor glycemic control
• Poor glycemic control
• Cardiovascular involvement
• peripheral neuropathy
• Diabetic nephropathy (especially patients on dialysis)
131
133. 133
• Sometimes termed
pigmented pretibial
papules, or “diabetic skin
spots,” begins as an
erythematous area and
evolves into an area of
circular hyperpigmentation
• Result from minor
mechanical trauma in the
pretibial region and are
more common in elderly
men with DM
Diabetic Dermopathy
134. 134
Necrobiosis Lipoidica Diabeticorum
•Rare ; predominantly affects
young women with T1DM,
neuropathy, and retinopathy
•Usually begins in the pretibial
region as an erythematous plaque
or papules that gradually enlarge,
darken, and develop irregular
margins, with atrophic centers
and central ulceration
•May be painful
136. Other Skin Lesions
• Generalized or localized granuloma annulare (erythematous
plaques on the extremities or trunk)
• Scleredema (areas of skin thickening on the back or neck at
the site of previous superficial infections) are more common in
the diabetic population.
• Lipoatrophy and lipohypertrophy can occur at insulin injection
sites but are unusual with the use of human insulin.
• Xerosis and pruritus are common and are relieved by skin
moisturizers
136
137. Definition
• Hypoglycemia is sometimes defined as a plasma glucose
45 to 50 mg/dL
⇒ an important framework for making the diagnosis of
hypoglycemia is Whipple’s triad:
(1) symptoms consistent with hypoglycemia
(2) a low plasma glucose concentration
(3) relief of symptoms by ↑ BS
137
138. Regulation of Glucose Homeostasis
• Despite wide variation of food intake & activity plasma
glucose are maintained within a narrow range, usually
between 60 - 150 mg/dL
• Between meals or during fasting, plasma glucose levels
are maintained primarily by the glycogenolysis and by
gluconeogenesis
• In most persons, hepatic glycogen stores are sufficient to
maintain plasma glucose levels for 8 to 12 hr
138
139. …continued
• As glycogen stores are depleted, glucose is generated
by gluconeogenesis, which occurs mainly in the liver
but also in the kidneys
• The balance of glucose production and its uptake
and utilization in peripheral tissues are exquisitely
regulated by a network of hormones, neural pathways,
and metabolic signals
139
140. Responses to Hypoglycemia in Normal Subjects
• Insulin plays a dominant and pivotal role
• In the fasting state, insulin is suppressed, allowing:
1- ↑Gluconeogenesis in the liver and kidneys
2- ↑Glucose generation by glycogenolysis
3-↓ Glucose uptake and utilization in peripheral tissues
4- Allow lipolysis and proteolysis to occur, which leads to
the release of precursors for gluconeogenesis
140
142. …continued
• As glucose levels approach to the hypoglycemic range, a
characteristic sequence of counterregulatory hormone
responses occurs
• Glucagon is the first and most important of these responses
(↑glycogenolysis &gluconeogenesis )
• Epinephrine play an important role in the acute response to
hypoglycemia, particularly when glucagon is insufficient.
It stimulates glycogenolysis & gluconeogenesis and limits
glucose
utilization by insulin-sensitive tissues
• When hypoglycemia is prolonged, GH and cortisol also reduce
glucose utilization and support its production
142
144. …continued
• The glucose thresholds at which various counter regulatory
hormone responses occur are dynamic and can be influenced by
recent metabolic events
• A person with poorly controlled diabetes can have symptoms of
hypoglycemia at higher than normal glucose levels
• Recurrent hypoglycemia, which may occur in individuals with
diabetes or an insulinoma, shifts thresholds for symptoms and
counterregulatory responses to lower glucose levels
144
145. 145
Common Symptoms of Acute Hypoglycemia
Neuroglycopenic Neurogenic (Autonomic)
Behavioral change Palpitation
Speech difficulty Tremor
Incoordination Anxiety
Confusion Sweating
Seizure Hunger
Loss of consciousness Paresthesia
146. Common Signs of Acute Hypoglycemia
• Pallor
• Diaphoresis
• Heart rate and the systolic blood pressure are
typically raised
• The neuroglycopenic manifestations are valuable,
albeit nonspecific, signs
• Transient focal neurologic deficits occur
occasionally
146
149. Endogenous Hyperinsulinism
(1) A primary pancreatic islet cell disorder, typically a cell
tumor (insulinoma)
(2) A cell secretagogue, often a sulfonylurea, and,
theoretically, a cell–stimulating autoantibody
(3) An autoantibody to insulin
(4) Ectopic insulin secretion
149
150. …continued
• The fundamental pathophysiologic feature of
endogenous hyperinsulinism is the failure of
insulin secretion to fall to very low rates
during hypoglycemia
• This is assessed by measuring insulin,
proinsulin, and C peptide
150
151. Critical Diagnostic Findings
• Plasma insulin ≥36 pmol/L (≥6 U/mL) and
• Plasma C-peptide ≥0.2 mmol/L (≥0.6 ng/mL)
• When the plasma glucose ≤45 mg/dL in the fasting state
with symptoms of hypoglycemia
• Insulin and C-peptide levels do not need to be absolutely
increased (e.g., relative to euglycemic normal values) but
only inappropriately increased in the setting of fasting
hypoglycemia
151
152. • Plasma proinsulin concentrations are also inappropriately
elevated, particularly in patients with an insulinoma
• Sulfonylureas, because they stimulate insulin secretion,
result in a pattern of glucose, insulin, and C peptide levels
that is indistinguishable from that produced by a primary β
cell disorder
• The measurement of sulfonylureas in plasma or urine
distinguishes these conditions
152
…continued
153. Insulinoma
• Rare
• Yearly incidence ≈ 1 in 250,000
• ≈ 90% benign
• 60% of cases occur in women
• Median age at presentation is 50 years in sporadic cases
• Usually presents in the third decade in MEN1
• Arise within the substance of the pancreas in 99% of cases
and are usually small (1 to 2 cm)
• Almost always recognized because of hypoglycemia rather
than mass effects
154
154. Response to Hypoglycemia in Diabetic Patients
• The protective response to hypoglycemia is impaired in many
diabetic patients
• Particularly when hypoglycemia is induced by insulin,
either directly from exogenous injection or indirectly
from sulfonylurea stimulation
• In these patients, insulin release cannot be turned off
• Furthermore, the effectiveness of counterregulatory hormones
is reduced
155
155. Impairment of Counter-regulatory Responses
• Glucagon response to hypoglycemia, becomes markedly
impaired or absent during the first few years in patients
with DM
• Epinephrine response also becomes impaired in many patients
later in the course of the disease
• Recurrent hypoglycemia itself also may contribute to the
impaired counter-regulatory response, potentially leading to
vicious cycle (hypoglycemia-associated autonomic failure)
156
156. 157
Main Causes of Hypoglycemia in DM
Mismatch of food and insulin/Drugs
Strict blood glucose control
Long duration of diabetes
Hypoglycemia associated autonomic failure
Exercise
↓ Endogenous glucose production (alcohol)
↓ Insulin clearance (renal failure)
159. • Even with a quantitative method, low
measured glucose concentrations can be arti
factual:
– e.g., the result of continued the result of
continued glucose metabolism by the formed
elements of the blood ex vivo, particularly in the
presence of leukocytosis, erythrocytosis, or
thrombocytosis or with delayed separation of
the serum from the formed elements
(pseudohypoglycemia
