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Diabetes Mellitus and Metabolic SyndromeBy: Susan Yu-Gan, MD, FPCP
Definition
• refers to a group of common metabolic disorders that share the phenotype of hyperglycemia.
• Defect in metabolism of carbohydrates, fats and proteins due to relative/absolute deficiency in insulin secretion or action
• Result in severe complications
Diabetes is a serious disease
Morales D et al. for the NNHeS 2003-2004 Group. PSH-PLS Convention. Feb 2005.
Sy R et al. PJIM. 2003; 41: 1.-6.
*FBS > 125 mg/dL **FBS ≥101 mg/dL
Population = 80 M
DM Prevalence:
• *FBS : 3.4 %
• ** FBS : 6.6 %
• FBS/history : 4.6 %
DM Local Prevalence Rate
Filipino DM : 3.4 M
Numbers Of People With Diabetes: Regional Figures For 2007 And Estimates For 2025
0
10
20
30
40
50
60
70
80
90
100
Nu
mb
ers
wit
h d
iab
etes
(m
illi
on
s)
AFR EMM EUR NA SAC SEA WP
Region
2007
2025
International Diabetes Federation. Diabetes Atlas, 3rd edn. Brussels: IDF, 2006.
AFR, Africa; EMM, Eastern Mediterranean; EUR, Europe; NA, North America;SAC, South and Central America; SEA, South -East Asia; WP, Western Pacific
The Epidemic of Type 2
• Rise in the prevalence and incidence of type 2 diabetes . Why?– Increased awareness, more diagnosed– New ADA and WHO criteria – Longer life span– Obesity– Geographic variations
• Potential huge economic burden - complications
Walking the dogWalking the dog
Unique Features Of The Diabetes Epidemic In Asia
The increase in type 2 diabetes in Asia developed: – in a shorter time– in a younger age group– in people with a much lower BMI – in people with a high predisposition to insulin
resistance at a lesser degree of obesity than people of European descent
Yoon KH et al. Lancet 2006; 368: 1681–8.
ADA. Screening for Type 2 Diabetes. Diabetes Care 2003; 26(Suppl1):s21-s24
Risk Factors for Type 2 DiabetesRisk Factors for Type 2 Diabetes
Patient Patient CharacteristiCharacteristi
cscs
Medical Medical HistoryHistory
Clinical Clinical FindingsFindings
Age > 45 years old
Family history Hypertension
Overweight/Obesity (BMI > 25
kg/m2)
Coronary artery disease
Dyslipidemia
Physical inactivity Cerebrovascular accidents
Race-Asians Previous history of IFG/IGT/GDM
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26 (Suppl 1) S5-20
Screening Recommendations
Mass screening for type 2 diabetes in the general population is not recommended (Grade D, consensus)
Testing for diabetes should be performed every 3 years in those over 45 years of age (Grade D, consensus)
Who Should Be Screened?• All adults 45 y/o; and, if normal,
at 3-yr intervals
• Younger age and more frequently in those at risk
– Obese
– First degree relative with diabetes
– High risk ethnic group
– Hx of GDM or delivered baby > 9 lbs.
– Hypertension (BP140/90)
– Dyslipidemia (HDL 35 mg/dL and/or triglyceride 250 mg/dL
– Previous IFG or IGT
ADA. Diabetes Care 2000: 23 (suppl 1); 54-519
Confirming the Diagnosis of Type 2 Diabetes mellitus
Only possible through serum glucose measurement
FPG 126 mg/dL (after 8 hr fast)
Random Plasma Glucose 200 mg/dL w/ classic diabetes symptoms– Polyuria, polydipsia, unexplained
wt loss
OGTT value 200 mg/dL in the 2-h sample
Confirmed on at least 2 occasions
A1c not routine test for diagnosis (2006)
Methods for Diagnosing DMMethods for Diagnosing DM
ADA. Diabetes Care 2000:23(suppl.1); 54-519
Normal Pre-Diabetes (IFG and
IGT)
Diabetes Mellitus
FPG <100 mg/dL (5.6 mmol/L)
100-125 mg/dL (5.6-6.9 mmol/L)
> 126 mg/dL (7.0 mmol/L)
2hPG < 140 mg/dL (7.8 mmol/L)
140-199 mg/dL (7.8-11.0 mmol/L)
> 200 mg/dL (11.1
mmol/L)
Levels of Glycemia
ADA. Standards of medical care in diabetes. Diabetes Care 2004; 27 (Suppl 1):S13-34
Impaired Glucose Tolerance (IGT) and Impaired Fasting Glucose (IFG)
• IGT and IFG refer to a metabolic stage intermediate between normal glucose homeostasis and diabetes
• IGT: 2hPG - 140 mg/dL to 199 mg/dL
• IFG: FBG - 100 mg/dL to 125 mg/dL
• Both are risk factors for future diabetes and cardiovascular disease
Etiologic Classification of Diabetes Mellitus
• Type 1 Diabetes
• Type 2 Diabetes
• Other specific types
• Gestational Diabetes Mellitus
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20
Type 1 Diabetes
• Results from autoimmune destruction of pancreatic beta-cells
• Absolute insulin deficiency
• Patients typically dependent on insulin for survival
• Patients may present with ketoacidosis as initial sign of the disorder
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20
Type 2 Diabetes
• Insulin resistance and relative insulin deficiency
• Patients may or may not need insulin treatment to survive
• May remain undiagnosed for many years, as hyperglycemia develops slowly
• Associated with strong genetic predisposition
• Heterogenous
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20
Other Specific Types
• Genetic defects of B cell function• Genetic defects in insulin action• Diseases of the exocrine pancreas• Endocrinopathies• Drug - or chemical - induced• Infections• Uncommon forms of immune-mediated
diabetes• Other genetic syndromes sometimes
associated with diabetes
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20
Gestational Diabetes Mellitus (GDM)
• Any degree of glucose intolerance with
onset or first recognition during pregnancy
• Associated with increased perinatal
morbidity and mortality
• 6 weeks or more after pregnancy ends, the
woman should be reclassified
• High risk for type 2 DM.
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20
Diagnosis of GDM with a 100-g or 75-g Glucose Load
mg/dL mmol/L
100-g Glucose Load Fasting 95 5.3
1 - h 180 10.0
2 - h 155 8.6
3 - h 140 7.8
75-g Glucose Load
Fasting 95 5.3
1 - h 180 10.0
2 - h 155 8.6
PANCREAS
• The pancreas is an elongated organ nestled next to the first part of the small intestine. The endocrine pancreas refers to those cells within the pancreas that synthesize and secrete hormones.
The endocrine portion of the pancreas takes the form of many small clusters of cells called islets of Langerhans or, more simply, islets. Humans have roughly one million islets.
• Pancreatic islets house three major cell types, each of which produces a different endocrine product:
• Alpha Cells (A cells) – secrete the hormone glucagon.
• Beta Cells (B cells) – produce insulin and are the most abundant of the islet cells.
• Delta Cells (D cells) – secrete the hormone somatostatin which is also produced by
a number of other endocrine cells in the body.
PANCREAS
Interestingly, the different cell types within an islet are not randomly distributed - beta cells occupy the central portion of the islet and are surrounded by a "ring" of alpha and delta cells. Aside from the insulin, glucagon and somatostatin, a number of other "minor" hormones have been identified as products of pancreatic islets cells.
PANCREAS
Structure of Insulin• Insulin is a rather small protein, with a molecular
weight of about 6000 Daltons.
• It is composed of two amino acid chains held together by disulfide bonds. When this two amino acid chains are split apart, the functional activity of insulin is lost.
• The amino acid sequence is highly conserved among vertebrates, and insulin from one mammal almost certainly is biologically active in another.
Insulin
INSULIN BIOSYNTHESIS
INSULIN BIOCHEMISTRY
Proinsulin- inactive chain of 86 a.a.
C Peptide- connecting peptide of 31 a.a.
Insulin – remaining 51 a.a. made up of chains A and B
INSULIN SECRETION
• Pancreas secrets 40-50 units insulin/day• Basal insulin conc. in fasting state 10 U/mL• Food ingestion, insulin conc.
8-10 min. initial increase
30-45 min peak
90-120 min. returns to baseline values.
• Control of Insulin Secretion
– Insulin is secreted primarily in response to elevated blood concentrations of glucose
– Some neural stimuli (e.g. site and taste of food) and increased blood concentrations of other fuel molecules, including amino acids and fatty acids, also promote insulin secretion.
– Glucose is transported into the B cell by facilitated diffusion through a glucose transporter; elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the B cell.
INSULIN
Control of Insulin Secretion
INSULIN
Parasympathetic Nervous System
Glucose Stimulus D i g e s t i v e
hormones
-Sympathetic nervous symtem
-Sympathetic Nervous system
Somastatin
Growth hormone ACTH
Glucagon
Insulin
+
+
+
+
+
+-
-
• Control of Insulin Secretion
– Elevated concentrations of glucose within the B cell ultimately leads to membrane depolarization and an influx of extra cellular calcium.
– The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules.
– An increased level of glucose within B cells also appears to activate calcium-independent pathways that participate in insulin secretion.
INSULIN
Volta
ge G
ate
dC
a C
han
nels
2+
Exocytosis of stored insulin
Ca2+
Glucose
Dep
olariz
atio
n
ATPproduction
K+
ATP sensitive Kchannel receptor
+
• Physiologic Effects of Insulin – Insulin is a key player in the control of
intermediary metabolism. – Insulin has profound effects on: – Carbohydrate metabolism
• Lipid metabolism• Significant influences on protein and mineral
metabolism• Consequently, derangements in insulin signaling
have widespread and devastating effects on many organs and tissues.
INSULIN
• The Insulin Receptor and Mechanism of Action– Like the receptors for other protein hormones, the receptor for insulin
is embedded in the plasma membrane.– The insulin receptor is composed of two alpha subunits and two beta
subunits linked by disulfide bonds. – The alpha chains are entirely
extra cellular and house insulin binding domains,while the linked beta chains penetrate through the plasma membrane.
INSULIN
• Insulin and Carbohydrate Metabolism– Insulin facilitates entry of glucose into muscle, adipose
and several other tissues.
– The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters of many tissues - muscle being a prime example
– The major transporter used for uptake of glucose called GLUT4 is made available in the plasma membrane through the action of insulin.
– Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose.
INSULIN
• Insulin and Carbohydrate Metabolism– It should be noted here that there are some tissues
that do not require insulin for efficient uptake of glucose: important examples are brain and the liver.
– This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.
– Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.
• When the supply of glucose is abundant, insulin “tells" the liver to bank as much of it as possible for use later.
INSULIN
Gluconeogenesis
Glycogenolysis
Glycogen synthesis
Lipogenesis
INSULIN EFFECTS ON LIVER
Glucose Uptake
Glycogen synthesis
Protein synthesis
INSULIN EFFECTS ON MUSCLE
Glucose uptake
Triglyceride synthesis
Lipolysis
INSULIN EFFECTS ON ADIPOSE TISSUE
• Insulin and Lipid Metabolism
– When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins.
– The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.
– Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.
INSULIN
• Other Notable Effects of Insulin
– Insulin also stimulates the uptake of amino acids, again contributing to its overall anabolic effect.
– Insulin also increases the permeability of many cells to potassium, magnesium and phosphate ions.
– The effect on potassium is clinically important. Insulin activates Na/K ATPase in many cells, causing a flux of potassium into cells.
INSULIN
What happens to glucose in the body? EXTERNAL
DIET
DIGESTION
GLUCOSE
Glycolysis ENERGY
Glycogen STORAGE
Lipogenesis FATS STORAGE
Glycogenesis
Glycogenolysis
Pyruvates
+
Lactates
Amino acidsGlycerol
INTERNAL
Gluconeogenesis(Liver)
What happens between meals?Blood Glucose
Liver mobilizes glycogen stores
Break down of Glycogen=
GLYCOGENOLYSIS
Glucose
Blood stream
N.B. The liver is the only organ able to liberate glucose from its glycogen stores
What happens after a meal?
Blood glucose Blood glucose
Insulin and Glucagon RegulateNormal Glucose Homeostasis
Glucose output Glucose uptake
Glucagon(α cell)
Insulin(β cell)
Pancreas
Liver MuscleMuscleAdipose Adipose
tissuetissue
Fasting state Fed state
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al,
eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
Major Pathophysiologic Defects in Type 2 Diabetes
Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168;
Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Hepatic glucoseoutput
Insulin resistance
Glucose uptake
Glucagon(α cell)
Insulin(β cell)
Liver
Hyperglycemia
Islet-cell Dysfunction
MuscleMuscleAdipose Adipose
tissuetissue
Pancreas
Incretin Hormones Regulate Insulin and Glucagon Levels
GLP-1 = glucagon-like peptide-1; GIP = glucose insulinotropic polypeptide Adapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes Care. 2003;26:2929–2940. Nauck MA et al.
Diabetologia. 1993;36:741–744. Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. Copyright © 1979 Springer-Verlag.
PancreasGut
Nutrient signals
● Glucose
Hormonal signals• GLP-1
• GIP
Glucagon(GLP-1)
Insulin (GLP-1,GIP)
Neural signals cells
cells
The Incretin Axis
Peptides released by the gut throughout the day and increased in response to meals — participate in normal glucoregulation
GLP-1 and GIP are the dominant incretins
Both stimulate insulin release from β-cells and GLP-1 inhibits glucagon release from -cells
The incretin axis is abnormal in patients with T2DM
Reduced release of GLP-1
Reduced response to GIP
Drucker DJ. Diabetes Care. 2003:2929-2940; Ahren B. Curr Diab Rep. 2003;3:365-372; Drucker DJ Gastroenterology. 2002;122:531-544.; Dunning BE, et al. Diabetologia. 2005;48:1700-1713.
ADA 2006 Late Breaking Clinical Presentation (Stein).
Demonstrated Effects of the Incretin HormonesGLP-1 and GIP
Is released from L cells in ileum and colon
Stimulates insulin response from β cells in a glucose-dependent manner
Inhibits gastric emptying
Reduces food intake and body weight
Inhibits glucagon secretion from α cells in a glucose-dependent manner
Effect on β-cell turnover in preclinical models
Is released from K cells in duodenum
Stimulates insulin response from β cells in a glucose-dependent manner
Has minimal effects on gastric emptying
Has no significant effects on satiety or body weight
Does not appear to inhibit glucagon secretion from α cells
Effect on β-cell turnover in preclinical models
GLP-1 GIP
Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606; Drucker DJ. Diabetes Care. 2003;26:2929–2940. Farilla L et al. Endocrinology. 2003;144:5149–5158.
Role of Incretins in Glucose Homeostasis
Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
Ingestion of food
β cellsα cells
Release of gut hormones —
incretins*
PancreasGlucose-dependent
Insulin from β cells(GLP-1 and GIP)
Glucose uptake
by muscles
Glucose dependent Glucagon from
α cells(GLP-1)
GI tract
ActiveGLP-1 & GIP
DPP-4 enzyme
InactiveGIP
InactiveGLP-1
*Incretins are also released throughout the day at basal levels.
Glucose production
by liver
Blood glucose in fasting and
postprandial states
Fate of Glucose
• If energy is needed immediately, glucose is metabolized to produce energy via glycolysis.
• If more glucose is available than what the cells need immediately for energy, the extra glucose is converted to glycogen via a process called glycogenesis. Glycogenesis occurs primarily in liver cells and, to a limited extent, in muscle cells.
• When glucose is not immediately required for energy and the storage capacity for glycogen is reached in the liver and muscle, additional glucose can be oxidized or converted to fat.
GLUT 4 Transporters
Before After
DeFronzo RA. Med Clin N Am 2004; 88:787–835.
Prevention Treatment–10 10 YearsDiagnosis
Macrovascular complicationsMacrovascular complications
0
IGT/IFG Type 2 diabetes
Natural History Of Disease Progression
Microvascular complicationsMicrovascular complications
Blood glucose
-cell function
Insulin resistance
Glucose Homeostasis
Pancreas
Insulin receptors
(GLUT 4)
Glucose transport proteins
Cell
Insulin Action in Normal Tissues (Cellular Level)
Insulin receptors
(GLUT 4)
Glucose transport proteins
Insulin Action in Normal Tissues (Cellular Level)
Cell
Insulin receptors
(GLUT 4)
Glucose transport proteins
Insulin Action in Normal Tissues (Cellular Level)
Cell
Insulin receptors
(GLUT 4)
Glucose transport proteins
Insulin Action in Normal Tissues (Cellular Level)
Cell
Insulin receptors
(GLUT 4)
Glucose transport proteins
Cell
Insulin Resistance
Insulin receptors
(GLUT 4)
Glucose transport proteins
Cell
Insulin Resistance
Insulin receptors
Cell
Insulin Resistance
Insulin receptors
(GLUT 4)
Glucose transport proteins
Cell
Insulin receptors
Cell
Insulin Resistance
INSULIN RESISTANCE Phase: Disease Progression Stage :
POST-Receptor Level Early stage - normal to IGT
Receptor Level Hyperinsulinemia- IGT to T2D
INSULIN RESISTANCE Phase: Disease Progression Stage :
Pre- Receptor Level Latter Part Stage - Beta-cell Dysfuntion
(Pancreatic exhaustion)
Pathogenesis of Type 2 Diabetes
ADA and IDF Guidelines:Treatment Goals for HbA1c, FPG, and PPG
ParameterNormalLevel
ADA Goal
IDF Goal
FPG, mg/dL(mmol/L)
<110(<6.1)
90–130(5.0–7.2)
<110 (<6.1)
PPG, mg/dL(mmol/L)
<140 (<7.8)
<180
(<10.0)
<145
(<8.1)
HbA1c 4%–6% <7%* <6.5%
*The HbA1c goal of an individual patient is to achieve an HbA1c as close to normal (<6%) as possible without significant hypoglycemia.
ADA=American Diabetes Association; IDF=International Diabetes Federation.
ADA. Diabetes Care. 2007;30(suppl 1):S4–S41; International Diabetes Federation. 2005:1–79.
Therapy for Type 2 DM
• Lifestyle changes– Diet– Exercise– Stop smoking– Glycemic control– Prevent complications– Prevent disease
progression
• Pharmacologic– Glycemic control– Prevent complications– Prevent disease
progression– Treat co-morbid
conditions– Minimal side effects
Nutrient Composition of the Therapeutic Lifestyle Change (TLC) Diet
Nutrient Recommended IntakeCarbohydrate 50% to 60% of total calories; mostly from
food rich in complex carbohydrates
Fiber 20-30 g/day
Protein Approximately 15% of total calories
Cholesterol <200 mg/day
Total Calories Balance energy intake and expenditure; should include at least moderate physical activity
Executive Summary of the Third Report of the National Cholesterol Education Program(NCEP) Expert Panel Detection, Evaluation, and Treatment of High Blood Cholesterol
in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497
Glucose
Adipose tissue
Gut
Stomach
Liver
BiguanidesMuscle
Pancreas
Sulphonylureas and meglitinides
Insulin
-glucosidase inhibitors
Thiazolidinediones
GLP-1
GLP-1 analogues
Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1(Suppl. 1):S32–S40.Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.Pratley RE & Salsali A. Curr Med Res Opin 2007; 23:919–931.Todd JF & Bloom SR. Diabet Med 2007; 24:223–232.
Primary Sites Of Action Of Oral Anti-diabetic Agents
DPP-4 inhibitors
DPP-4
Insulin Secretagogues: Basic Characteristics
• Mechanism of action:– Increase basal and postprandial insulin secretion
• Therapeutic efficacy:– Decreases HbA1c 1%-2%*
• Recommended dosing:– Sulfonylureas: 1-2x daily – Repaglinide, nateglinide: 3x daily
• Adverse effects:– Weight gain, hypoglycemia
*Results vary according to clinical trial design, individual patient characteristics, and data analyses.
Amaryl PI. Hoechst Marion Roussel, August 1997; DiaBeta PI. Hoechst Marion Roussel, September 1997; Glucotrol PI. Pfizer, September 1993; Glynase PI. Pharmacia & Upjohn, February 1999; Micronase PI. Pharmacia & Upjohn, January 1999; Prandin PI. Novo Nordisk, October 1998.
Sulfonylureas
• Tolbutamide
• Chlorpropamide
• Glibenclamide/Glyburide
• Gliclazide
• Glipizide
• Glimepiride
Guideline for Use of SULFONYLUREAS
Action Generic Trade Name Preparation Daily Dose
Short Tolbutamide Rastinon 500 mg tablet 1/2 - 6 tabs
Inter-mediate
Glibenclamide
Gliclazide
Glipizide
Glimepiride
EugluconDaonil
Orabetic
Diamicron MRDiamicron DianormGlubitor
Minidiab OD
SolosaNorizec
2.5/5.0 mg tab5.0 mg tablet5.0 mg tablet
30 mg tablet
80 mg tablet80 mg tablet
5/10 mg tab
1,2,3 mg tab
1/2 - 3 tabs
1 - 4 pre-breakfast
1/2 - 4 tabs
½ -6 tabs1-4 mg
Long Acting
Chlorpropamide Diabenese 250 mg tablet 1/2 - 2 tabs
Meglitinides
• Also stimulates insulin secretion by the pancreas
• Shorter acting than sulfonylureas
• Targets the postprandial elevation of blood sugar
Meglitinides
• Repaglinide
• Nateglinide
Biguanides (Metformin)
• Suppresses hepatic glucose output
• An insulin sensitizer
• May cause Lactic acidosis
• Contraindicated in patients with hepatic and renal insufficiency and in patients with hypoxemia
MetforminAction Reduce liver glucose production
Insulin sensitivity Yes (liver predominantly)
Hepatic glucose output Reduced
Serum insulin No effect
Hypoglycaemia No
Lipids Reduced
Onset of action Moderate
Weight Neutral or reduced
Effectiveness over time Reduced
Safety GI effectsDrug interactionsRenal insufficiency (Lactic acidosis)
Alpha-glucosidase inhibitors§ Three agents marketed: acarbose
voglibose andmiglitol
§ Inhibit the alpha-glucosidase enzyme involved inthe breakdown of complex carbohydrates intoglucose and other simple sugars in the intestine
§ Delay the absorption of carbohydrates following meals
§ Acarbose is positioned for treatment of mealtimeglucose spikes
§ Suitable for combination with sulfonylureas
Acarbose
Action Reduced glucose absorption
Insulin sensitivity No effect
Hepatic glucose output No effect
Serum insulin No effect
Hypoglycaemia No effect
Lipids No effect
Onset of action Moderate
Weight Neutral or reduced
Effectiveness over time Uncertain (at 3 years)
Safety GI effectsHepatic (LFT elevation)Drug interactions (few
Thiazolidinediones
• Insulin sensitizers
• Acts by activation of PPAR
• Must monitor liver enzymes
• Side effects include fluid retention, edema, anemia
Thiazolidinediones
• Troglitazone
• Rosiglitazone
• Pioglitazone
Hepatic (Inc LFT in Troglitazone)Drug interactions (few)Weight gain ? Edema ?
Safety
DurableEffectiveness over time
IncreasedWeight
Moderate to lateOnset of action
Generally positiveLipids
No effectHypoglycaemia
DecreasedSerum insulin
Slight decreaseHepatic glucose output
IncreasedInsulin sensitivity
Insulin sensitizerAction
Thiazolidinediones
Indications for Insulin in Type 2 Diabetes
• Hyperglycemia despite maximum doses of oral agents
• Decompensation due to intercurrent events e.g., infection, acute injury, or other stress
• Development of severe hyperglycemia with ketonemia and/or ketonuria
• Uncontrolled weight loss
Indications for Insulin in Type 2 Diabetes
• Perioperative in patients undergoing surgery
• Pregnancy
• Renal or hepatic disease
• Allergy or other serious reaction to oral agents
Tier 1: Well-validated core therapiesTier 1: Well-validated core therapies
At diagnosis:
Lifestyle+
Metformin
STEP 1STEP 1
Tier 2: Less well-validated therapies
Lifestyle + Metformin+
Intensive insulin
STEP 3STEP 3
Lifestyle + Metformin + GLP-I agonists
No hypoglycemiaWeight loss
Nausea/vomiting
Lifestyle + Metformin + Pioglitazone
No hypoglycemiaOedema/CHF
Bone loss
Lifestyle + Metformin+
Basal insulin
Lifestyle + Metformin+
Sulfonylurea
STEP 2STEP 2
Lifestyle + Metformin+ Pioglitazone+ Sulfonylurea
Lifestyle + Metformin+ Basal Insulin
Algorithm for the Metabolic Management of Algorithm for the Metabolic Management of Type 2 DiabetesType 2 Diabetes
DiabeticRetinopathy
Leading causeof blindness
in adults1,2
DiabeticNephropathy
Leading cause of end-stage renal disease3,4
CardiovascularDisease
Stroke
2- to 4-fold increase in
cardiovascular mortality and stroke5
DiabeticNeuropathy
Leading cause ofnon-traumatic lower
extremity amputations7,8
8/10 individuals with diabetes die from CV
events6
Type 2 diabetes is associated with serious complications
1UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:1–11. 2Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 3The Hypertension in Diabetes Study Group. J Hypertens 1993; 11:309–317. 4Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 5Kannel WB, et al. Am Heart J 1990; 120:672–676.
6Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences. 7King’s Fund. Counting the cost. The real impact of non-insulin dependent diabetes. London: British Diabetic Association, 1996. 8Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.
Hyperglycemia
Neuropathy– Peripheral– Autonomic
Biology of Microvascular Complications
Kidney Nerves
RetinopathyCataractGlaucoma
Nephropathy– Microalbuminuria– Gross albuminuria
Blindness Kidney failure Amputation
Death and/or disability
Eye
Metabolic injury to large vessels
Heart Brain Extremities
Cardiovascular disease Acute coronary
syndrome Myocardial infarction
(MI) Congestive heart
failure
Cerebrovascular disease Transient
ischemic attack Stroke Cognitive
impairment
Peripheral vascular syndrome Ulcers Gangrene Amputations
Biology of Macrovascular Complications
Impact of Type 2 Diabetes on Macrovascular Disease
• Largest cause of morbidity and mortality
• Risk of CVD increased 2- to 4-fold
• Higher case fatality vs non diabetic individuals
• Reduced survival post–MI, post–CABG, and particularly post–PTCA
• Risk of stroke and peripheral vascular disease substantially increased
Betteridge DJ. Acta Diabetol. 1999;36:S25-S29. Nesto R. Acta Diabetol. 2001;38:S3-S8.
Diabetic Macroangiopathy
• Atherosclerosis– Atherosclerosis begins to appear in most diabetics
whatever their age, within a few year of onset of diabetes.
– The susceptibility of diabetics to atherosclerosis is due to several factors:
• Hyperlipidemia• HDL Levels are reduced in type 2 diabetics • Diabetics have increased platelet adhesiveness and
response to aggregative agents.
• Most type 2 diabetic patients are obese and hypertensive
which further contributes to Atherosclerosis
CLINICAL PRESENTATION OF MACROANGIOPATHY
• Stroke– Estimated relative risk of stroke in diabetes mellitus:– 2 – 8%– Mainly due to the atherosclerosis of the cerebral vessels
leading to the rupture and ischemia of the cerebral tissue.
• Coronary Heart Diseases√ Ischaemic heart disease – Type 2 diabetics develop CHD at a young age– The 5-Years risk of ischaemic events is doubled– Worse outcome post –MI
PATHOPHYSIOLOGY OF THE DIABETIC FOOT
PATHOPHYSIOLOGY OF THE DIABETIC FOOT
atherosclerosis Of the leg vessels
Infection(contributes to
tissue necrosis)
Peripheral neuropathy
claudication ulceration gangrene rest pain
Ischemia (Often bilateral) Sensory deficit
Autonomic dysfunction
Diabetic Neuropathy
• Numbness, tingling or pain in the toes, feet, legs, hands, arms and fingers
• Wasting of muscles of feet or hands• Indigestion, nausea or vomiting• Diarrhea or constipation• Dizziness or faintness due to a drop in postural
blood pressue• Problems with urination• Erectile dysfunction (impotence) or vaginal
dryness• Weakness
INFECTIONS
Hyperglycemia favors Development of infection
Urinary tract Infection
Skin infection
Respiratory tract infection
Treatment of infectionAnd improved blood glucose
Control
DIABETIC RETINOPATHY
One of the most threatening aspects of DM’s the development of visual impairment
• Epidemiology
– Leading cause of blindness in Western countries– Retinopathy is the most common complication of diabetes.– Risk factors are: duration of diabetes, poor BG control,
high– Blood pressure, hypercholesterolemia, proteinuria.
• Symptoms– Reduction in visual
acuity
– Reduction in visual fields
– Reduction in vision of colors
DIABETIC RETINOPATHY
DIABETIC NEPHROPATHY
• A major cause of end-stage renal disease and dialysis.
• The kidneys are usually the most severely damaged organs in diabetics
• Diabetic nephropathy with proteinuria is a common serious complication affecting Type 1 and Type 2 diabetes.
• Affect 25% of the diabetics
Natural History of Diabetic Nephropathy
Definition of Abnormal Albumin Excretion
UAER UAER Urinary(mg/24H) (mcg/min)
albumin/
creatinine
(mg/gm)
Normal < 30 < 20 < 30
Microalbuminuria 30 – 300 20 – 200 30 – 300
Macroalbuminuria > 300 > 200 > 300
Measurements
• Albumin to creatinine ratio
• 24 hour urine collection
• Timed collection (4 H or overnight)
• Screen for with reagent strips
False Positives
• Short time hyperglycemia
• Exercise
• Acute febrile illness
• UTI
• Marked hypertension
• CHF
Microvascular Complications of Diabetes
Stage UAE
Rate
(μg/min)
Blood
Pressure
Glomerular
Filtration rate
(GFR)
Histological
Changes
1
Hyperfiltration
0 – 20 Normal Increased by
20 – 50 %
Increased
Glomerular size
1
Normoalbuminuria
0 – 20 Normal Increased by
20 – 50 %
Basement
Membrane (BM)
thickening
2
Microalbuminuria
21 – 200 Normal or
elevated
Still high, but
declines with
proteinuria
BM thickening
Mesangial
expansion
3
Proteinuria
>200 Elevated Decline
~10ml/min/yr
Pronounced
abnormalities
4End-stage renal
Failure
>200 Hypertension <10ml/min Advanced
glomerulopathy
Stages of diabetic nephropathy(Adapted from Mogensen 1999)
Risk Factors DM Nephropathy
Poor glycemic control and insulin resistance
Hypertension
Albuminuria
Smoking
High dietary intake of protein
Hyperlipidemia
Microvascular Complications of Diabetes
• Microalbuminuria predicts cardiovascular morbidity and mortality as well as renal disease
• Treatment should delay or prevent the progression of microalbuminuria to proteinuria
• Trials have shown that therapeutic strategies should include:
- intensive glycaemic control
- aggressive control of blood pressure (ACE inhibitors)
Diabetic Nephropathy: Therapeutic Strategies
Treatment Recommendations for Diabetic Patients with Albuminuria/Nephropathy
• In the treatment of albuminuria/nephropathy, both ACE inhibitors and ARBs can b used:
– In hypertensive and non-hypertensive T1 DM: ACE-inhibitors are the initial agents of choice
– In hypertensive and non-hypertensive T2 DM: ARBs are the initial agents of choice
Diabetes Care. 2002;25(1):S33
Strategies for Preventing Complications of Diabetes
• Control blood glucose– HbA1c below 7%– FBS below 110 mg%– RBS below 160 mg%
• Control blood pressure– Below 130/80
• Control lipids– LDL below 100 mg%– HDL above 45 for males and 55 for females– Triglycerides below 150 mg%
• Weight loss• Stop smoking
Summary of Recommendations for Adults With Diabetes
Glycemic Control
A1C <7.0%*
Preprandial plasma glucose 90-130 mg/dL (5.0-7.2 mmol/L)
Postprandial plasma glucose† <180 mg/dL (<10.0 mmol/L)
Blood pressure <130/80 mmHg
Lipids‡
LDL <100 mg/dL (<2.6 mmol/L)
Triglycerides <150 mg/dL (<1.7 mmol/L)
HDL >40 mg/dL (1.1 mmol/L)§*Nondiabetic range of 4.0-6.0% using DCCT-based assay†PPG made 1-4 h after beginning of meal
‡NCEP/ATP III guidelines: for TG>200 mg/dL, use non-HDL cholesterol = TC-HDL§For women, HDL goal >50 mg/dL
Diabetes Care 2004; 27(Suppl1):S15-S35
What is the Metabolic Syndrome
• A group of metabolic risk factors in one person. • Central obesity • Atherogenic dyslipidemia - mainly high triglycerides and
low HDL cholesterol • Insulin resistance or glucose intolerance• Prothrombotic state (e.g., high fibrinogen or plasminogen
activator inhibitor [–1] in the blood) • Raised blood pressure (130/85 mmHg or higher) • Proinflammatory state (e.g., elevated high-sensitivity C-
reactive protein in the blood)
Clinical Identification - Any 3 of the followingMetabolic Syndrome
LOW HDL-C Men < 40 mg/dL (1.0 mmol/L)
Women < 50 mg/dL (1.2 mmol/L)
HIGH Triglycerides≥ 150 mg/dL(≥ 1.7 mmol/L)
Abdominal ObesityMen > 40 inches (>102 cm)
Women > 35 inches (>88 cm)(Waist circumference)
Hypertension ≥ 130 / ≥ 85 mmHg
Fasting Glucose≥100 mg/dL≥ 5.5 mmol/L
NCEP-ATP III – JAMA 2001
New IDF Definition of Metabolic Syndrome
Waist circumference Plus 2 of the
ff: (cm)
Europids FBS >5.6 (100mg/dL) >94 male >80 female TRIG >1.7 (150mg/dL) South Asians >90 male HDL < 0.9 (<40mg/dL) M >80 female <1.1
(<50mg/dL) F Chinese >90 male BP >130 systolic >80 female >85
diastolic Japanese >85 male >90 female www.idf.org
Prevalence (%)1998 2003-2004
Low HDL 65 54Obesity (BMI>30) 3.2 5Obesity (WHR 1/0.85) 34.9Smoking 34.8 Hypertriglyceridemia 9 21 Hypertension 17.2 17.4 DM 3.9* 3.4*
4** 4.6** 6.6 ***
Metabolic Syndrome (NCEP) 14.2 12.4
Morales D et al. for the NNHeS 2003-2004 Group. PSH-PLS Convention. Feb 2005.
Sy R et al. PJIM. 2003; 41: 1.-6.
*FBS > 125 mg/dL ** FBS or history *** FBS ≥101 mg/dL
Risk Factors Among Filipinos
genetic predisposition excess body fat (abdominal
obesity) sedentary lifestyle physical inactivity
Ford ES et al. JAMA. 2002; 287: 356-9.
Risk Factors for Metabolic Syndrome
• While the pathogenesis of the metabolic syndrome and each of its components is complex and not well understood, central obesity and insulin resistance are acknowledged as important causative factors.
IDF Consensus 2004Recommendations for Treatment
• Primary InterventionIDF recommends that primary management for
the MS is healthy lifestyle promotion. This includes :
* moderate calorie restriction ( to achieve a 5-10% loss of BW in the 1st year )
* moderate increase in physical activity
* change in dietary composition
IDF Consensus 2004Recommendations for Treatment
• Secondary intervention * In people for whom lifestyle change is not
enough and who are considered to be at high risk for CVD, drug therapy may be required to treat the metabolic syndrome.
* However, specific pharmacological agents are not yet available.
* It is currently necessary instead to treat the individual components of the metabolic syndrome.
IDF recommended treatment of the individual components of the metabolic syndrome.
• Atherogenic dyslipidemia Primary aims for therapy : * Lower Tg * Raise HDL * Reduce LDL
Options : * Fibrates * Statins
IDF recommended treatment of the individual components of the metabolic syndrome.
• Elevated blood pressure In patients with established diabetes, anti-
HPN therapy should be introduced at BP ≥130/≥80 mmHg.
Options : * ACEI and ARB. Effect of lowering of BP
per se more important than the drug itself? * No particular agents have been identified
as being preferable for HPN patients with MS.
IDF recommended treatment of the individual components of the metabolic syndrome.
• Insulin resistance and hyperglycemia There is growing interest in the possibility
that drugs that reduce IR will delay the onset of type 2 DM and will reduce the CVD risk when the MS is present.
Cardiovascular Risk Factors and Therapies
↑ LDL cholesterol
↓ HDL cholesterol
↑ Triglycerides
↑ Blood Pressure
↑ Blood Glucose
↑ Waist Circumference
↓ Insulin Sensitivity
↑ Thrombotic risk
Lipid Modifiers
Anti-hypertensives
Anti-diabetic agents
Weight Loss Agents + Diet and exercise
Insulin sensitizers
Anti-platelet agents
NCEP-ATP III / IDF
criteria for the
metabolic syndrome