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Rainier Icamina
Diabetes Mellitus (DM)
Classification
Based on pathogenic process that leads to
hypoglycemia
Type 1 DM
Type 2 DM
Diabetes Mellitus (DM)
Classification
Type 1 DM
Type 1A DM
– autoimmune beta cell destruction which leads to
insulin deficiency
Type 1B DM
– lack immunologic markers indicative of an
autoimmune destructive process of the beta cells.
However, they develop insulin deficiency by
unknown mechanisms and are ketosis prone
Diabetes Mellitus (DM)
Classification
Type 2 DM
– Heterogeneous group of disorder characterized by variable degrees of insulin
resistance, impaired insulin secretion and increase glucose production.
Other Types of DM
Maturity Onset Diabetes Of The Young (MODY)
– Subtype of DM characterized by autosomal dominant inheritance, early onset
of hyperglycemia and impairment of insulin secretion
Diabetes Mellitus (DM)
Classification
Gestational Diabetes Mellitus (GDM)
Insulin resistance related to metabolic
changes of late pregnancy, increase insulin
requirements and may lead to IGT
Most women revert to normal glucose
tolerance post-partum but have a substantial
risk (30 – 60%) of developing DM later in life
Diabetes
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Diabetes Mellitus (DM)
Epidemiology
Prevalence has risen the past two decades
Type 2 DM expected to rise more
Age
Prevalence increase with age
– 0.19% < 20 yo
– 8.60% > 20 yo
– 20.1% > 65 yo
Gender
Similar to men and women at all ages but slightly
greater in men > 60 yo
Diabetes Mellitus (DM)
Epidemiology
Geographic Variation
Type 1 DM
– Scandanavia, Northern Europe, United States
Type 2 DM
– Certain Pacific Islands, India, United States
Diabetes Mellitus
Risk Factors
Family History of Diabetes
Obesity (BMI > 25 kg/m2)
Race/ethnicity
(African, American, Hispanic American, Native American, Asian
American, Pacific Islander)
Previously identified IFG or IGT
Diabetes Mellitus
Risk Factors
History of GDM or delivery of baby > 4kg (>9lbs)
Hypertension (140/90)
HDL < 35mg/dl (0.90mmol/L) and/or Triglyceride level > 250 mg/dl
(2.82 mmol/L)
Polycystic ovary syndrome or acanthosis nigricans
History of vascular disease
Insulin
Biosynthesis
Preproinsulin
Produced in beta
cells of pancreatic
islet
Proinsulin
Receptor
Stimulate Intrinsic
Tyrosine Kinase Activity
Widespread Metabolic
and Mitogenic Effects
Insulin
Action
Insulin
Action
Glucose uptake
Glycogen synthesis
Protein synthesis
Lipogenesis
Regulation of various genes in insulin – responsive cells
Insulin
Insulin
Secretion
Diabetes Mellitus (DM)
Pathogenesis Type 1 DM
Genetic susceptible
individuals
complete
destruction
Diabetes Mellitus
Pathophysiology of Type 2 DM
Insulin resistance
Impaired insulin production
Increase hepatic glucose production
Diabetes Mellitus
Pathophysiology of Type 2 DM
Insulin resistance
Result from combination of genetic
susceptibility and obesity
– Adipocytes – secret biologic products that
modulate insulin secretion and action (leptin,
TNF-a, FFA, resin and adiponectin)
Pathophysiology of Type 2 DM
Insulin resistance
Result from combination of genetic
susceptibility and obesity
– Adipocytes – secret biologic products that
modulate insulin secretion and action (leptin,
TNF-a, FFA, resin and adiponectin)
Glucose toxicity
– Chronic hyperglycemia impairs islet function
Lipotoxicity
– Elevation of FFA and dietary fat worsens islet
function
Diabetes Mellitus
Increase hepatic glucose production
Diagnosis
Diagnostic Criteria
Diabetes Mellitus
Glucose tolerance
Normal
FPG < 5.6 mmol/L (100mg/dl)
IFG
FPG > 5.6 - < 7.0 mmol/L (126mg/dL)
DM
FPG > 7.0 mmol/L
The Roles of A1C
Surrogate marker for risk of
diabetic complications
Useful assessment of glycemic
control during clinical
management
Proposed future measure for
screening or confirming the
diagnosis of diabetes
21
Diabetes Mellitus
Diabetes Mellitus
Acute Complications
Diabetic Ketoacidosis (DKA)
Result from relative or absolute insulin deficiency
Combined with counter regulatory hormone excess
Absence of Ketosis
Diabetes Mellitus (DM)
Hyperglycemic Hyperosmolar State
Relative insulin deficiency and inadequate fluid intake
Absence of Ketosis
Diabetes Mellitus (DM)
Hyperglycemic Hyperosmolar State
Clinical features
Polyuria
Weight loss
Diminished oral intake
Mental confusion
Lethargy or Coma
Diabetes Mellitus (DM)
Hyperglycemic Hyperosmolar State
PE
Profound dehydration
Hyperosmolality
Hypotension
Tachycardia
Diabetes Mellitus (DM)
Laboratories
Diabetes Mellitus (DM)
Management for DKA
Diabetes Mellitus (DM)
Management for HHS
Fluid replacement
1 to 3 L 0.9% normal saline - initial
0.45% saline initially then 5% dextrose in D5W
Potassium repletion
Diabetes Mellitus (DM)
Management for HHS
Fluid replacement
1 to 3 L 0.9% normal saline - initial
0.45% saline initially then 5% dextrose in D5W
Potassium repletion
Diabetes Mellitus (DM)
Chronic Complications
Divided into 2
Vascular
– Microvascular
– Macrovascular
Non Vascular
Diabetes Mellitus (DM)
Chronic Complications
Divided into 2
Vascular
– Microvascular
– Macrovascular
Non Vascular
Diabetes Mellitus
Chronic Complications
Mechanism is unknown
4 prominent theories
Formation of advanced glycosylation end products (AGEs)
Sorbitol pathway of glucose metabolism
Formation of protein kinase C (PKC)
Hexosamine pathway
Diabetes Mellitus
AGEs
Formed via non-enzymatic glycosylation of intra and
extracellular proteins
Cross-link protein, accelerate atherosclerosis,
promote glumerular dysfunction, reduce nitric oxide
synthesis, induce endothelial dysfunction, and alter
extracellular matrix composition and structure
Serum levels correlates with levels of glycemia
Diabetes Mellitus
Sorbitol Pathway
Intracellular glucose
predominantly metabolize by phosphorelation and glycolysis
converted to sorbitol by enzyme aldose reductase
Increased sorbitol concentration alters redox potential, increase
cellular osmolality, generates reactive oxygen species
Leads to other types of cellular dysfunction
Diabetes Mellitus
PKC
Hyperglycemia increase the formation of diglycerol
leading to activation of PKC
Prolifertive
Complications
Diabetic Retinopathy
Nonproliferative
– Appears late in the first decade or early in the second decade
– Characterize by : retinal vascular microaneurysm
blot hemorrhages
cotton wool spots
Pathologic mechanism
Retinal ischemia
– Loss of retinal pericytes
– Increase retinal vascular permiability
– Alterations in retinal blood flow
– Abnormal retinal microvasculature
Complications
Diabetic Retinopathy
Proliferative
Neovasccularization in response to retinal hypoxia
Newly formed vessels appears near the optic nerve and/or macula and rupture easily
Leads to vitreous hemorrhage
–
Fibrosis
–
Retinal detachment
–
Complications
Complications
Renal Complications
Diabetic Nephropathy
Leading cause of ESRD in US
Leading cause of DM related morbidity and mortality
Most patient have diabetic retinopathy
Mechanism:
Hemodynamic alterations in renal microcirculation
Structural changes in the glumerulus
Complications
Diabetic Nephropathy
sequence
1st yr 1 – 5 yrs 5 – 10 yrs
Glomerular Thickening of Excrete small
hyperperfusion glomerular basement amt of albumin
Renal Hypertrophy membrane in urine
GFR Glomerular hypertrohy 40%
Mesingial volume
expansion Progress to overt
GFR n proteinuria
50%
ESRD 7 – 10yrs
Complications
Diabetic Nephropathy
Type 2 DM nephropathy
Microalbuminuria or overt nephropathy may be present at time of
diagnosis
Hypertension
Microalbuminuria is less predictive of diabetic nephropathy and
progression of overt nephropathy
Complications
Diabetic Nephropathy
Treatment
Prevention is the optimal therapy
– detection of microalbuminemia at an early stage when effective
therapies can be instituted
Complications
Diabetic Nephropathy
Treatment
Prevention is the optimal therapy
detection of microalbuminemia at an early stage when effective therapies can be instituted
–
Complications
Diabetic Nephropathy
Treatment
Interventions effective in slowing progression:
Near normalization of glycemia
– Strict blood pressure control
– Administration of ACE inhibitors and ARBs
– Treatment of dyslipidemia
–
Complications
Diabetic Nephropathy
Treatment
Interventions effective in slowing progression:
Near normalization of glycemia
– Strict blood pressure control
– Administration of ACE inhibitors and ARBs
– Treatment of dyslipidemia
–
Complications
Diabetic Nephropathy
Treatment
ACE inhibitors and ARBs
Reduce progression of nephropathy
– Repeat measurement of proteinuria after 2 – 3 moths of therapy
–
Clinical findings
– Tachycardia and orthostatic hypotension
– Gastroparesis
– Bladder emptying abnormalities
– Hyperhydrosis of upper extremities and anhidrosis of feet
Complications
Neuropathy
Treatment
Glycemic control
Avoidance of alcohol
Vitamin suppliments
Symptomatic treatment
Bethanechol
Sildenafil
Erectile dysfunction
–
Complications
Cardiovascular
Cardiovascular disease is increased in individuals with type 1 or 2 DM
Marked increased (5 fold):
Peripheral arterial disease
Congestive heart failure
– Coronary artery disease
– Myocardial infarction
– Sudden death
–
–
PCI
CABG
Complications
Cardiovascular
Treatment
Risk factors:
– Dyslipidemia
– Hypertension
Complications
Diabetes
Treatment
Overall principle:
Eliminate symptoms related to
hyperglycemia
Reduce or eliminate long term microvascular
and macrovascular complications
Allow patient to achieve normal lifestyle if
possible
Diabetes Mellitus
Treatment Type 1 DM
Establishment of a target level of
glycemic control
Diabetes Mellitus
Treatment
Nutrition
Goal is to coordinate and match caloric
intake, both temporally and quantitatively,
with the appropriate amount of insulin.
Diabetes Mellitus
Treatment
Nutrition
Goal is to coordinate and match caloric
intake, both temporally and quantitatively,
with the appropriate amount of insulin.
Diabetes Mellitus
Treatment
Exercise
Cardiovascular risk reduction
Reduce blood pressure
Reduction in body fat
Treatment
Intensive management
Goal is to achieve euglycemia or near-
normal glycemia
– Patient education
– Comprehensive recording of plasma glucose
measurement and nutritional intake
– Variable insulin regimen that matches glucose
intake and insulin dose
Diabetes Mellitus
Treatment
Intensive management
Goal is to achieve euglycemia or near-
normal glycemia
– Patient education
– Comprehensive recording of plasma glucose
measurement and nutritional intake
– Variable insulin regimen that matches glucose
intake and insulin dose
Diabetes Mellitus
Treatment
Insulin
Treatment
Insulin Preparations
Normal Daily Plasma Insulin
Profile
µ U/mL
100
B L D
80
60
40
20
Time of day
B=breakfast; L=lunch; D=dinner
Action Profiles of Insulin Analogues
Plas
ma
Aspart, lispro 4–6 hours
insul
in Regular 6–8 hours
level NPH 12–20 hours
s
Ultralente 18–24 hours
Glargine 24 hours
0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324
Hours
Diabetes Mellitus
Treatment for Type 1 DM
One common use regimen consist of twice daily injection of (NPH or
lente) mixed with short acting insulin before morning and evening meal
Effective in avoiding severe hyperglycemia
It does not generate near normal glycemic control
Enforce rigid schedule for the patient
Diabetes Mellitus
Treatment for Type 1 DM
One common use regimen consist of twice daily injection of (NPH
or lente) mixed with short acting insulin before morning and
evening meal
Effective in avoiding severe hyperglycemia
It does not generate near normal glycemic control
Split-Mixed Regimen
Human Insulins
NPH NPH
Regular Regular
µ U/mL
100
B L D
80
Normal pattern
60
40
20
Time of day
B=breakfast; L=lunch; D=dinner
Diabetes Mellitus
Treatment for Type 1 DM
Multiple-component insulin regimen
Combination of:
– Basal insulin
– Preprandial short acting insulin
60
40
20
Time of day
B=breakfast; L=lunch; D=dinner
Treatment
Management of type 2 DM
Goal is similar to type 1 DM
Glycemic control
Treatment of conditions associated with type 2
DM
Detection and management of DM complication
Treatment
Management of type 2 DM
Treatment
Management of type 2 DM
Glucose lowering agent
Increase insulin secretion
Reduce glucose production
Increase insulin sensitivity
Treatment
Management of type 2 DM
Treatment
Treatment
Management for Type 2 DM
Insulin
Initial therapy for DM
Management of type 2 DM
Treatment
Insulin Secretagogues
Sulfonylureas, Repaglinide, and Nateglinide
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