This document provides an overview of diabetes mellitus and its management. It discusses the hormones of the islets of Langerhans, the pathophysiology of type 1 and type 2 diabetes, insulin resistance, diagnosis, complications, and management. The key objectives are to understand the role of islet cells, etiology and pathophysiology of diabetes types, risk factors, symptoms, HbA1c, diagnosis, management, and complications of diabetes.
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1. Diabetes Mellitus &
and Management
Presented by Dr Phanavarine.
Advisor: Bun Se. Leang,MD
SIHANOUK HOSPITAL CENTER OF HOPE
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Objective
• Know H of the islets of Langerhans.
• Know the role of counterregulatory H
• Etiology and path-physiology type I & II DM
• Risk factor/ Classification/ Symptoms
• HbA1c
• Diagnosis
• Management
• Complication
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HORMONES OF THE
ENDOCRINE PANCREAS
• Adult pancreas ~ 1 million islets,
mostly in the tail, constitute < 3% of
pancreatic mass.
• There are four major cell types in the
islets of Langerhans:
– cell - glucagon,
– cell - insulin
– cell - somatostatin,
– F (or PP) cell - pancreatic polypeptide.
• Human insulin
– Protein, 6000 MW, 51 aa, two
polypeptide chains
– A chain = 21 aa, linked to B chain by
two disulfide bridges.
– Synthesis and stored in -cells
secretory granules
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There are four major cell types in the
islets of Langerhans :
– cells- produce glucagon. Glucagon is catabolic, mobilizing
glucose, fatty acids and amino acids from stores into the
blood stream; tends to increase plasma glucose by
stimulating hepatic glycogenolysis and gluconeogenesis;
increases lipolysis in adipose tissue.
– cells - produce insulin. Insulin is anabolic, increasing
the storage of glucose, fatty acids and amino acids.
– cells - produce somatostatin, which inhibits secretion of
insulin, glucagon and pancreatic polypeptide.
– F (or PP) cells - responsible for the production of
pancreatic polypeptide, which slows absorption of food.
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Byproduct of the synthesis of insulin
Indirect measurement of insulin level
Help in distinction between DM 1 and 2
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Biosynthesis of Insulin
• Insulin is synthesized in the rough
endoplasmic reticulum of β cells
• Insulin is synthesized as a part of a larger
preprohormone called preproinsulin
• Connecting peptide or C-peptide
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The flux of K+ is regulated
by intracellular ATP
A surge in blood glucose
leads to increased ATP
production, hence influx
of Ca++ and fusion of
insulin granules to the
membrane and
exocytosis to the
bloodstream.
Glycemia
Postprandial pulse Insulin secretion
(Glucose induced insulin secretion)
K+
Insulin
depolarisation
Glu t-2
+
+
+
-
-
-
+
+
-
- -
+
cell
ATP
glucose
G-6-P
GK
PK
pyruvate
Krebs
cycle
Ca2+
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Basal insulin secretion
Normal glycemia => glucose cannot
enter beta cells => no ATP => ATP
sensitive K+ channels open => K+ out
=> keeps membrane potential at -
70mV => no potential action =>
voltage gated Ca2+ channel closed
and no insulin secretion. Pacemaker
beta cells stimulate every 10 minutes
the voltage gated Ca2+ channel =>
open => insulin is released ~ 20 units
daily (50% of daily need).
Pacemaker
ß
cells
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The Bi-phasic Insulin Response
Adapted from Howell SL. Chapter 9. In: Pickup JC, Williams G (Eds). Textbook of Diabetes. Oxford. Blackwell Scientific Publications 1991: 72–83.
1st phase, rapid burst first few min.
Usually responds to G, aa,
sulfonylurea, glucagon and
gastrointestinal (GI) hormones.
2nd phase, after about 10 min and
continues for as long as 1 hr:
is stimulated by G and aa
Adult human secretes ~ 40-50 units of
insulin per day, of which:
~ 50% is unstimulated or “basal”
(preprandial)
the remaining is secreted as pulses
in response to food
(postprandial).
Loss of this pulsatile secretion is one of
the earliest signs of beta-cell
dysfunction in patients destined to
have DM I.
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Insulin
receptor
Plasma membrane
GLUT4 vesicle mobilization
to plasma membrane
Glucose
Insulin
Intracellular
signaling
cascades
Insulin Action in Muscle and Fat Cells
Mobilization of GLUT4 to the Cell Surface
GLUT4 vesicle
integration into
plasma membrane
Glucose entry into cell
via GLUT4 vesicle
Intracellular
GLUT4 vesicles
GLUT4=Glucose Transporter 4
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Insulin Resistance and Insulin
Hypersecretion
precede Type 2 Diabetes
Insulin Insulin Macrovascular
sensitivity secretion disease
30% 50% 50%
50% 70–100% 40%
70% 150% 10%
100% 100%
Adapted from: Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721
IGT
Impaired
glucose
metabolism
Normal glucose
metabolism
Type 2
diabetes
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Insulin receptor
Insulin receptors are present in almost all cells of the
body. It is a glycoprotein tetramer made of 2 α and 2 β
subunits linked by disulfide bridges.
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Mechanism of action of insulin
• Binding of insulin to the α subunits of the receptors
triggers tyrosine kinase activity of the β subunits,
producing autophosphorylation of the β subunits on
tyrosine residues.
• This autophosphorylation triggers phosphorylation or
dephosphorylation of some cytoplasmic proteins or
enzymes so that some enzymes are activated and
some inactivated, thus bringing about the actions of
insulin.
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Effects of insulin
Rapid (seconds):
Increased transport of glucose, amino acids, and K+ into insulin
sensitive cells.
Intermediate (minutes):
• Stimulation of protein synthesis
• Inhibition of protein degradation
• Activation of glycogen synthase and increased glycogenesis
• Inhibition of phosphorylase and gluconeogenic enzymes
(decreased gluconeogenesis)
Delayed actions (hours):
• Increase in mRNAs for lipogenic and other enzymes
(increased lipogenesis)
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On carbohydrate metabolism..
Reduces rate of release of glucose from the liver by
• inhibiting glycogenolysis
• stimulating glycogen synthesis
• stimulating glucose uptake
• stimulating glycolysis
• inhibiting gluconeogenesis
Increases rate of uptake of glucose into all insulin sensitive
tissues, notably muscle and adipose tissue.
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On lipid metabolism…
• Reduces rate of release of free fatty acids from
adipose tissue.
• Stimulates synthesis of fatty acids and also
conversion of fatty acids to triglycerides in liver.
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On protein metabolism…
• Stimulates transport of free amino acids
across the plasma membrane in liver and
muscle.
• Stimulates protein synthesis and reduces
release of amino acids from muscle.
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Actions……
• Insulin favors movement of potassium into cells
Vigorous treatment with insulin (as in DKA) will
cause potassium to move into cells causing
hypokalemia.
• Promotes general growth and development.
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The fundamental defects are…
• Reduced entry of glucose into various peripheral
tissues
• Increased liberation of glucose into circulation
from liver. Therefore there is an extracellular
glucose excess and in many cells an intracellular
glucose deficiency.
• Various signs and symptoms in diabetes are due
to disturbances in carbohydrate, protein and lipid
metabolism.
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Consequences of disturbed carbohydrate
metabolism
• Polyuria, polydypsia and polyphagia are seen in some
diabetic patients.
• The renal threshold for glucose is 180 mg/dl i.e. if the
plasma glucose value is raised above 180 mg/dl,
• glucose will start appearing in urine (glycosuria).
• glucose is lost in the urine, it takes along with it water
(osmotic diuresis) leading to increased urination
(polyuria).
• Since lot of water is lost in the urine, it leads to
dehydration and increased thirst (polydypsia).
Electrolytes are also lost in the urine.
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Consequences of disturbed carbohydrate
metabolism….
• The quantity of glucose lost in urine is enormous
and thus to maintain energy balance the patient
takes in large quantities of food.
• Also because of decreased intracellular glucose,
there is reduced glucose utilization by the
ventromedial nucleus of hypothalamus (satiety
center) and is probably the cause for the
hyperphagia.
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Consequences of disturbed lipid
metabolism
• The principal abnormalities are acceleration of lipid catabolism
with increasing formation of ketone bodies and decreased
synthesis of fatty acids and triglycerides.
• Acidosis and ketosis is due to overproduction of ketone
bodies (acetoacetate, acetone and β-hydroxybutyrate).
• Most of the hydrogen ions liberated from acetoacetate and β-
hydroxybutyrate are buffered, but still severe metabolic acidosis
still develops.
• The low pH (metabolic acidosis) stimulates the respiratory
center and produces the rapid, deep, regular kussmaul
breathing.
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Consequences of disturbed lipid
metabolism….
• The acidosis and dehydration can lead to coma and
even death.
• Lipase converts triglycerides to free fatty acids (FFA)
and glycerol. Insulin inhibits the hormone sensitive
lipase in adipose tissue and in the absence of insulin,
the plasma level of FFA doubles. In liver and other
tissues, the FFA are catabolised to acetyl Co A, and the
excess acetyl Co A is converted to ketone bodies.
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Consequences of disturbed protein
metabolism
• There is increased protein breakdown leading
to muscle wasting
• Decreased protein synthesis
• Increased plasma amino acids and nitrogen
loss in urine leading to negative nitrogen
balance and protein depletion.
• Protein depletion is associated with poor
resistance to infections.
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Consequences of disturbed cholesterol
metabolism
• In diabetics, the cholesterol level is usually elevated
leading to atherosclerotic vascular disease.
• This is due to a rise in the plasma concentration of
VLDL and LDL (which maybe due to increased
production by the liver or decreased removal from
circulation).
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Effects of insulin deficiency
• Carbohydrate Metabolism
• Protein Metabolism
• Lipid Metabolism
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Definition
• Diabetes mellitus is a metabolic disease
characterized by hyperglycemia resulting from
defects in insulin secretion, insulin action or both.
• The chronic hyperglycemia of diabetes mellitus is
associated with long term damage, dysfunction and
failure of various organs, especially retina, kidney,
nerves, and increased risk of cardiovascular
disease.
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Classification of Various Hyperglycemias
• Diabetes Mellitus (DM)
– Type 1 diabetes
• Immune Mediated
• Idiopathic
– Type 2 diabetes
• Individuals with insulin resistance who usually have relative rather than
absolute insulin deficiency (obese or non-obese)
– Other types of diabetes
• Pancreatic disease and pancreatic surgery
• Endocrinopathies due to overproduction of counter-regulatory hormones
• Drug-induced
– Gestational diabetes (GDM)
• Impaired Glucose Tolerance (IGT)
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Pathogenesis of Type I DM
Environment ?
Viral infe..??
Genetic
HLA-DR3/DR4
Severe Insulin deficiency
ß cell Destruction
Type I DM
Autoimmune Insulitis (GAD,ICA IAA)
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Pathogenesis of Type II DM
Environment
Obesity
ß cell defect
Genetic
ß cell
exhaustion Type II DM
Insulin resistance
Relative Insulin Def.
May require
Insulin
Secretory Defect
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Insulin Resistance (IR) in DM II
• IR = insulin responsive tissues are insensitive to insulin, thus insulin secretion
is stepped up to compensate, and results in hyperinsulinemia.
• IR in the muscle (here G transport is mediated by GLUT4) is the hallmark of
DM II and may be the initial event in cascade of DM.
• This brings about down regulation of insulin receptors with subsequent of G
transporters leading to persistent hyperglycemia and chronic beta cells
stimulation, eventually burn out the beta cells leading to insulinopenia.
• IR at early stages may be reversible with any modality that reduces
hyperglycemia (i.e., diet and exercise, or treatment with insulin or oral
hypoglycemic agents) which leads to reduction of insulin, improves insulin
sensitivity and reverses IR.
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The hall mark of type 2 DM is insulin resistance, where glucose uptake and metabolism
is reduced by about 50% in the muscle.
The major sites of insulin resistance in type 2 DM are in muscle tissue and liver.
38. The Concept of the Metabolic Syndrome
"Metabolic Syndrome" (a.k.a.
Syndrome X or Insulin Resistance
Syndrome) describes a cluster of
CVD risk factors and metabolic
alterations associated with excess
fat.
WHO clinical definition:
IGT / IFG/T2DM + any of the
two below:
1. Increased Waist-Hip
Ratio (M:>0.9, F:>0.85)
2. Elevated BP > 140/90
mm Hg
3. Elevated
Triglycerides>150mg/dl
4. Low HDL cholesterol
5. Microalbuminuria
Untreated metabolic syndrome
has 30% risk of having either
stroke, heart attack or angina
within the next 5 years.
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Calculation for Ideal Body Weight (IBW), Body Mass Index (BMI)
and Recommendation for Proper Dietary Composition
• Ideal Body Weight (IBW)
– Women 100 lb for first 5 feet + 5 lb for each additional inch
– Men 110 lb for first 5 feet + 6 lb for each additional inch
• Body Mass Index [BMI = Wt.(kg)/height (M)2]
– normal value 19-22
– obese >25
• Calorie Requirement
– Basal requirement Ideal body weight x 10
– Average activity Add 30% to basal requirement
– Strenuous activity Add 100% - 200% to basal requirement
– Weight loss Subtract 500 calories/day to lose 1 lb/week
– Pregnancy Add 300 calories/day
– Lactation Add 500 calories/day
• Dietary Composition
– Carbohydrate 50% - 55% of total calories
– Protein 15% - 20% of total calories
– Fat 30% of total calories (<10% saturated fat)
– Fiber 30 gm soluble fiber
1 pound = 454g
1 foot = 0.3048m
1 inch = 2.54cm
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MORNING HYPERGLYCEMIA IN
INSULIN-TREATED DIABETES
• 3 reasons for morning hyperglycemia in an insulin
treated diabetic (type 1 or 2):
– the dawn phenomenon,
– waning of insulin,
– post-hypoglycemic hyperglycemia (Somogyi
phenomenon).
• Dawn phenomenon = Physiologic hyperglycemia
started from 3 a.m.
– counterregulatory effect of growth hormone (GH)
after REM sleep.
• Somogyi phenomenon, BS levels usually decrease
to the hypoglycemic or near- hypoglycemic range
and may cause counterregulatory hormone
secretion.
• Thus, morning hyperglycemia => first assume that
it may be due to Somogyi phenomenon => either
reducing the dose of insulin that is active overnight
or increasing the pre-bedtime snack. If morning
hyperglycemia is not reduced by this method, it is
likely that waning insulin or a dawn phenomenon
is responsible, and overnight insulin coverage
should be increased.
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Risk factors for diabetes
• Family history, first degree relative with DM
• Obesity
• Age greater than 45 years
• History of gestational diabetes or delivering a
baby weighing more then 4 kg.
• High blood pressure, Bp 140/90 mm hg
• High blood cholesterol level
• Previous IFG or IGT
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IFG IGT GDM
≥ 100 ≥100 ≥ 99
and <126 and < 126
< 140 ≥ 140 and or ≥ 144
< 200
or FPG ≥ 126 mg/dL
(≥ 2x)
(≥ 2x)
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WHO criteria/ plasma glucose
• Diabetes Mellitus:
– 1. Fasting Blood Sugar 7mmol/l or 126mg/dl
– 2. 2-h plasma glucose after eating 11.1
( 200mg/dl)
• Impaired glucose tolerance ( IGT):
– Fasting < 7mmol/l ( 126mg/dl) and
– 2-h plasma glucose after eating 7.8 ( 140) to <11.1(200)
• Impaired fasting glycemia (IFG):
– Fasting 6.1 (110) to < 7 ( 126 )
– 2-h plasma glucose < 7.8 ( < 140
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Major Characteristics
of DM I and DM II
Features Type 1 DM Type 2 DM
Age at onset Usually <40 Usually >40
Proportion of all diabetes About 10% About 90%
Appearance of symptoms Acute/subacute Slow or subacute
Metabolic Ketoacidosis Frequent Rare***
Obesity at onset Uncommon Common
ß-Cells Variable
Insulin or absent Variable
Family history of diabetes Uncommon Common
HLAAssociation Yes No
Ab to islet cells (ICA) Yes Uncommon
Insulin autoAb (IAA) Yes No
Treatment Insulin and diet Diet, wt, exercise, OHA**, Insulin
** Oral hypoglycemic agents; *** Except in African-Americans
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Glycosylated (Glycated) Hemoglobin
• Under normal conditions, G attaches covalently (non-enzymatic glycosylation) to
the valine molecule of the chain of Hgb A (which is 90% of all Hgb) in the RBC
which leads to a stable subtype HbA1c.
• The reaction is slow and irreversible, the rate is proportional to the glycemia levels
over the 120 days life of RBC. Non-diabetes have HbA1C ~ 3-6.5%.
• Thus, its value reflects chronic glycemic control over the past 3-4 months.
• Any condition that alters erythrocyte turnover lowers HbA1c levels (i.e., bleeding,
pregnancy or splenectomy).
• On the other hand, uremia, fetal Hb, aspirin or high levels of ethanol may falsely
elevate levels of HbA1c.
• These interfering substances do not affect HbA1c levels measured by more specific
methods such as affinity chromatography.
48. If HbA1c is: HbA1c * Average SMBG is:
1 percentage point above normal 7% ~ 150 mg/dL (8.3 mmol/L)
2 percentage point above normal 8% ~ 180 mg/dL (10.0 mmol/L)
3 percentage point above normal 9% ~ 210 mg/dL (11.7 mmol/L)
4 percentage point above normal 10% ~ 245 mg/dL (13.6 mmol/L)
5 percentage point above normal 11% ~ 280 mg/dL (15.6 mmol/L)
6 percentage point above normal 12% ~ 310 mg/dL (17.2 mmol/L)
7 percentage point above normal 13% ~ 345 mg/dL (19.2 mmol/L)
8 percentage point above normal 14% ~ 380 mg/dL (21.1 mmol/L)
* assumes normal range of 4-6%
Nathan, DM, et al: N Engl J Med 1984; 310: 341-346.
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Diabetes Prevention Program (DPP)
• Background
– lifestyle and obesity => IGT => DM II
• Objective
– Can we prevent IGT from developing DM II
• Method
– 3,234 IGT enrolled
– 3 arms: lifestyle intervention, metformin 850 mg BID, placebo
– average follow-up of 2.8 years
• Result
– weight loss of 7% through lifestyle intervention reduced incidence of
diabetes by 58% as compared to placebo group
– metformin (850 mg twice daily) reduced the incidence by 31%, as
compared to the placebo group
– rate of conversion of IGT to DM II was not significantly different
among ethnic groups, ranging from 10-11% per year.
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Treatment
• There is no cure for diabetes.
• The immediate goals of treatment are to stabilize the blood
sugar and eliminate the symptoms of high blood sugar.
• The long-term goals of treatment are prevent long-term
complications such as heart disease and kidney failure.
• Education, diet, exercise, weight control, medication,
blood glucose self-testing, and foot care are vital for good
control of diabetes and prevention of its complications.
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How to manage Type II DM
• Nutritional therapy;
– Achieve glucose, lipid, and blood pressure goals
as first objective
– Weight loss goals are second objective
– Focus on food choices, spacing meals, and
caloric reduction of weight loss
– Exercise
– Behavior modification
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Oral Diabetes Medications
• People with type 2 diabetes tend to have two problems:
– they don’t make quite enough insulin.
– the cells of their bodies don’t seem to take in glucose as
eagerly as they should.
• We have five classes of drugs: sulfonylureas, meglitinides,
biguanides, thiazolidinediones, and alpha-glucosidase
inhibitors.
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Management of DM type 2
29-Apr-06 Sihanouk Hospital Center of HOPE 60
Medical Nutrition Therapy
Good response continued
No response Start Medication
BMI < 22
BMI > 22
Glucophage(b)
Add Sulfonylurea(a)
Sulfonylurea (a)
Add Glucophage (b)
strike diet/exercise
-fine out of injection, IHD, …
-Add Insulin [at evening dose], or
-third oral Medication of
Different class (c)
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Sulfonylureas
• Sulfonylureas stimulate the beta cells of the
pancreas to release more insulin.
• This drugs have been in use since the 1950s.
– Actions- increased insulin secretion
– Phamacokinetic- metabolized by liver and excreted by
kidney.
– Side effects- increased risk of hypoglycemia, weight
gain.
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Sulfonylureas
• First-generation : Chlorpropamide( brand name
Diabinese), still in use today, Dose: 100-500mg PO qd
with breakfast
• Second generation: Glyburide ( Micronase, Glynase, and
Diabeta) 2.5- 20 mg PO qd with breakfast or bid. Glipizide
( Glucotrol and Glucotrol XL) more potent and exhibits
fewer drug interactions, Dose: 2.5-40 mg/d PO. Daonil
2.5- 15 mg qd PO.
• Third-generation: Glimepiride (Amaryl)1-8 mg PO qd with
breakfast
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Meglitinides
• Are drugs that also stimulate the beta cells to release
insulin.
• Repaglinide ( Prandin) and nateglinide (Starlix) 0.5-4 mg
PO, each of three meals, up to qid.
• Most useful in patient at increased risk for hypoglycemia.
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Biguanides
• Metformin ( Glucophage).
• Actions: decreased hepatic glucose production,
increased peripheral glucose uptake, reduced
weight gain, no effect on insulin secretion.
• Decreases HbA1c 1.5%-2%
• Adverse effects: diarrhea, cramping, gas,
• Does- 500mg- 3 g PO bid, up to tid with meals.
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Thiazolidinediones
• Rosiglitazone (Avandia), troglitazone (Rezulin), and
pioglitazone (ACTOS).
• Actions: Improves insulin sensitivity, reduced insulin
resistance, decreased hepatic glucose output, increased
peripheral glucose uptake.
• Decreases HbA1c 0.5%-1.3%
• Side effects: weight gain, liver function failure.
• Cautions: monitor transaminases, discontinue if ALT
rises above 3X upper limit of normal,
• Dose: Rosiglitazone 4-8 mg/d or divided bid, Actos-15-
30 PO qd
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Alpha-glucosidase inhibitors
• Acarbose (Precose) and meglytol (Glyset).
• Actions- help the body to lower blood glucose levels by
blocking the breakdown of starches, such as bread,
potatoes, and pasta in the intestine. Delay digestion and
absortion of complex carbohydrate,mallose and sacrose.
• Decrease HbA1c 0.5%-1%
• Side effects: abdominal discomfort, diarrhea
• Dose: 25-100 mg per meal.
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General Principle
• One drug will lower:
– HbA1c by 1.5%-2%
– Fasting blood glucose by 40-60md/dl
• Don’t substitude when 1 drug fail, add…
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Step guide to insulin treatment in type 2DM
• Step1: check diet, activity and oral medication are appropriate and that
complicating medical conditions are not present.
• Step2:Dicide the time and type of insulin.
– Morning glucose evening glucose Schedule
– High OK Night-time intermediate or ultralente
– OK High Morning intermediate
– High High Twice daily intermediate
• Step3:Decide the dose: Start low and go slow (eg:1/3 ideal body weight)
– Single dose morning or evening
– Twice daily dose 2/3 morning, 1/3 evening
– less may be required in elderly, active, thin pt & more in overweight & underactive
• Step4: Adjust doses:
• Change doses in increments of 10%-20% at intervals of 2-4 days
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Prognosis
• At the end of the 10 years, the study showed that
those people with the best control of blood glucose
and blood pressure had
• 32% decreased risk of all diabetes-related deaths,
• 44% decreased risk of stroke,
• 56% decreased risk of heart failure,
• 37% decreased risk for micro-vascular (small
blood vessel) complications.
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References
1. UpToDate 12.2, CD-ROM released 2004, Endocrinology section.
2. Carey; C.F; et al. The Washington Manual of Medical Therapeutics, 30th
edition, 2003, Ch. Endocrine Diseases.
3. Nowak, T.J.; Handford, A.G. Essentials of Pathophysiology, 1994, Ch.
Endocrine.
4. McPhee, S.P.; Lingappa, V.R.; Ganong, W.F.; Lange; J.D. Pathophysiology
of Disease, 1994, Ch. Endocrine.
5. Pathophysiology Course – Endocrine Module, 2003, at
http://www.utmem.edu/endocrinology
6. Abboud, C.F.; Vella, A. Endocrinology, Mayo Clinic Internal Medicine
Review, Certification and Recertification, CD-ROM released 2003.
7. Hines, G.J. Endocrinology lectures series, Sihanouk Hospital Center of
HOPE, 2003.
8. Saladine; S.K, Anatomy and Physiology, 2nd edition, 2001.
9. Diabetes Management in General pratice.2005.