Type II Diabetes
Heidi Chamberlain Shea, MD
Endocrine Associates of Dallas
Points of Discussion
Type II Diabetes





Background
Diagnosis
Pathophysiology
Oral treatments
Office visits
Type II Diabetes

Epidemic




Parallels the rise in
obesity
Genetics


Increase intake
Decreased activity
Obesity causes earlier
disease
High risk ethnic groups

Indian, African American
and Hispanic
Obesity Trends* Among U.S. Adults
(*BMI 30, or about 30 lbs overweight for 5’4” person)
1991
1996
2003
No Data
<10%
10%–14%
15%–19%
20%–24%
≥25%
Type II Diabetes


Insulin resistance
ß-Cell secretory
dysfunction




Relative insulin
deficiency
Onset in puberty
Acanthosis
Nigricans
Female
Diagnosis of Diabetes
ADA Expert Committee
Symptoms of diabetes plus a random plasma glucose
concentration of  200 mg/dL, regardless of the time
since last meal
FASTING
(8 hrs)
NORMAL
< 110 mg/dl
(6.1 mM)
IMPAIRED
110-125
mg/dl
DIABETES
>= 126 mg/dl
(7 mM)
ORAL
GTT*
< 140 mg/dl
(7.8 mM)
140-199
mg/dl
>=200 mg/dl
(11.1 mM)
* Not recommended for routine clinical use
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2002;25 Suppl 1
Metabolic
Consequences
in Type 2 DM
Impaired insulin secretion
Increased Hepatic
Decreased
Muscle
Glucose
uptake
Glucose Production
Insulin
Resistance
Etiology of Type 2 Diabetes
Impaired Insulin Secretion and Insulin
Resistance
Genes and environment
Impaired insulin
secretion
+
Insulin resistance
Impaired glucose
tolerance
Type 2 diabetes
Low Insulin Secretion and Sensitivity
Both Predict Progression from IGT to
Type 2 Diabetes
Cumulative
diabetes
incidence
over 4 years
40
30
20
Low
10
High
0
Low
High
Early-phase insulin secretion
IGT=impaired glucose tolerance
Weyer C et al. Diabetes Care. 2001;24:89-94
Decline of -Cell Function in the
UKPDS Illustrates Progressive Nature of
Diabetes
-cell function 100
(% of normal by
HOMA)
80
Time of diagnosis
?
60
40
Pancreatic function
= 50% of normal
20
0
10 9 8 7 6 5 4 3 2 1 0
HOMA=homeostasis model assessment
Years
Adapted from Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25;
UKPDS. Diabetes. 1995;44:1249-1258
1
2
3
4
5
6
High FFA Levels Cause
Peripheral and Hepatic Insulin Resistance
Glucose Measurements During High Insulin Levels
500
Insulin
Insulin + fat infusion
400
300
*
200
*
100
0
FFA=free fatty acid
Peripheral
glucose uptake
Boden G, Chen X. J Clin Invest. 1995;96:1261-1268
Hepatic
glucose output
*P<0.05
Mechanism of Glucotoxicity and
Lipotoxicity
The Glucosamine Hypothesis
Glucose
FFA
Glucose
Other
pathways
FFA
Increased
glucosamine
Impaired insulin
secretion from -cell
Other
pathways
Insulin resistance
in muscle and fat
FFA=free fatty acid
Hawkins M et al. J Clin Invest. 1997;99:2173-2182; Rossetti L. Endocrinology.
2000;141:1922-1925
Etiology of Type 2 Diabetes
Impaired Insulin Secretion and Insulin Resistance
Genes and environment
Impaired insulin
secretion
Insulin resistance
Impaired glucose
tolerance
Type 2
diabetes
Progressive hyperglycemia
and high free fatty acids
Better Insulin Secretion
After Improved Metabolic Control
Response to Oral Glucose Before and After 3 Therapies
Diet
n=17
Plasma insulin
(U/mL)
Sulfonylureas
n=26
Insulin
n=7
50
*
*
*
*
*
25
*
*
* *
*
*
*
*
After
*
*P<0.05
*
Before
*
0
0
1
2
3
0
*
1
2
Hours
Kosaka K et al. Diabetologia. 1980;18:23-28
3
0
1
2
3
Regulation of Fasting Glucose
• Hepatic glucose production is a primary factor
determining fasting plasma glucose
• Fasting hepatic glucose production is regulated by
– Fasting (basal) plasma insulin
– Hepatic sensitivity to insulin
– Fasting substrate availability
• In type 2 diabetes
– Basal insulin secretion is impaired
– Hepatic sensitivity to insulin is decreased
Hepatic Resistance to Insulin
in Type 2 Diabetes
Hepatic Glucose Output During Graded Insulin Infusion
Glucose output
(mg/m2/min) 100
•
•
50
0
Normal
Type 2 diabetes
*
•
*
• •
•
0
*P<0.05
•
•*
50
•*
•
100
150
Calculated portal plasma insulin (U/mL)
Groop LC et al. J Clin Invest. 1989;84:205-213
• •
Impaired Basal Insulin Secretion in
Type 2 Diabetes
Insulin Secretion Rate During Graded Glucose Infusion
30
Secretion/BMI
25
pmol x m2/(min x kg)
Normal
IGT
Type 2 diabetes
20
15
10
5
0
100
IGT=impaired glucose tolerance
BMI=body mass index
150
200
Plasma glucose (mg/dL)
Byrne MM et al. Am J Physiol. 1996;270(4 pt 1):E572-E579
250
300
Regulation of Postprandial Glucose
• A meal contains 6 to 20 times the glucose
content of the blood
• Normally, postprandial hyperglycemia is
regulated by
– Clearance of ingested glucose by the liver
– Suppression of hepatic glucose production
– Peripheral clearance of glucose
Impaired Regulation of
Postprandial Glucose
• In impaired glucose tolerance or diabetes,
glucose regulation is impaired by
– Delayed and reduced insulin secretion
– Lack of suppression of glucagon
– Hepatic and peripheral insulin resistance
Abnormal Acute Insulin Response to
Intravenous Glucose in Type 2 Diabetes
Plasma insulin
(U/mL)
Type 2 Diabetes
Normal
100
1 00
80
80
Glucose
60
60
40
40
20
20
0
0
– 30
0
30
Glucose
– 30
Minutes
Robertson RP, Porte D Jr. J Clin Invest. 1973;52:870-876
0
30
OGTT-Stimulated Insulin Release in
IGT and Type 2 Diabetes
Insulin release
(IR/G [pM/mM])
120
100
80
60
40
20
0
OGTT=oral glucose tolerance test
NGT=normal glucose tolerance
IGT=impaired glucose tolerance
Kahn SE et al. Diabetes. 1998;47:640-645
NGT
n=56
IGT Type 2 diabetes
n=28
n=10
Patterns of Glucose, Insulin, and Glucagon
After Oral Glucose in Type 2 Diabetes
Postprandial hyperglycemia
Type 2 Diabetes
300
Normal
200
100
–60
0
60
180
Delayed and reduced
240
120
0
240
300
60
Minutes
360
Insulin (pmol/L)
120
Glucagon (fmol/L)
Glucose (mg/dL)
400
–60
0
60
120
180
240
Minutes
Mitrakou A et al. Diabetes. 1990;39:1381-1390
300
High and not suppressed
45
30
–60
0
60
120
Minutes
180
240
300
Insulin Resistance in IGT and
Type 2 Diabetes
Glucose
disposal rate
(mg/m2/min)
360
270
180
90
0
Normal
IGT=impaired glucose tolerance
Kolterman OG et al. J Clin Invest. 1981;68:957-969
IGT
Type 2 diabetes
Peripheral Insulin Sensitivity Decreases
With Intra-abdominal Fat
Intraabdominal
fat (cm3)
300
Females
r = -0.44
P=0.0024
250
200
150
100
Males
50
0
Females
0 1
2
3 4 5 6
7 8 9 10 11
Insulin sensitivity (x 10-4 min-1 • U-1 • mL-1)
Cefalu WT et al. Metabolism. 1995;44:954-959
Males
r= -0.68
P=0.005
Abnormal Glucose and Insulin Profiles
in Type 2 Diabetes
Glucose
(mg/dL) 400
Insulin 120
(U/mL)
Type 2 on diet only
Normal
100
300
80
200
60
40
100
20
0600 1000 1400 1800 2200 0200 0600
B
D
L
0600 1000 1400 1800 2200 0200 0600
L
D
B
Time of day
B=breakfast; L=lunch; D=dinner
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239
Summary of Pathophysiology
• Type 1 diabetes
– The main abnormality is insulin deficiency
• Type 2 diabetes
– Both insulin deficiency and insulin resistance
contribute
–Free Fatty Acids
–Increased Glucagon
• Glucotoxicity and lipotoxicity
– Poor metabolic control worsens insulin
deficiency and insulin resistance
Summary of Pathophysiology

Basal hyperglycemia
Basal insulin levels
 Hepatic response determine fasting plasma glucose


Postprandial hyperglycemia
Early insulin release
 Glucagon suppression
 Hepatic and muscle responses to insulin determine
postprandial glucose

Pharmacologic Treatment

Insulin
Secretagogues
Sulfonylureas
 Meglitanides


Insulin Sensitizers
Metformin
 Thiazolidinediones
α-Glucosidase inhibitor
 Acarbose, miglitol



Insulin
Sulfonylureas
Older
Newer




Glyburide
 Micronase,
Diabeta
Glyburide
 Glynase
Glipizide
 Glucotrol
 Glucotrol XL
Glimepiride
 Amaryl




Chlorpropamide
 Diabenase
Tolazamide
Acetohexamide
Dymelor
Tolbutamide
Insulin Secretion by the -Cell
Roles of Glucose, K+, and Ca2+
Glucose entry
Insulin secretion
GLUT2 glucose
transporter
Insulin secretory granules
Glucokinase
Ca2+
Glucose metabolism
K+
ADP/ATP
Ca2+
K+ K+
ADP/ATP
SUR 1
Kir 6.2
K+
Potassium (KATP)
KATP channel subunits:
channel
SUR 1=regulatory subunit;
Kir 6.2=inward rectifying channel closes
Ca2+
Ca2+
Ca2+
Calcium
channel
opens
Insulin Secretagogues
Sulfonylureas, Repaglinide, and Nateglinide
Mechanism of action
Increase basal and/or postprandial
insulin secretion
Efficacy depends upon
Functioning -cells
Power
Sulfonylureas, repaglinide: decrease A1C
1%–2%
Nateglinide: decreases A1C 0.5%–1%
Dosing
Sulfonylureas: 1 or 2 times daily
Repaglinide, nateglinide:
3 or 4 times daily with meals
Side effects
Weight gain, allergy (rare)
Main risk
Hypoglycemia
Riddle MC. Am Fam Physician. 1999;60:2613-2620; Wolffenbuttel et al. Drugs. 1995;50:263-288;
Horton ES et al. Diabetes Care. 2000;23:1660-1665; Hanefeld M et al. Diabetes Care. 2000;23:202-207;
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: ADA; 1998
Biguanides
Metformin
Primary mechanism
of action
Decreases hepatic glucose
production
Efficacy depends upon
Presence of insulin
Power
Dosing
Decreases A1C 1%–2%
2 or 3 times daily
(metformin)
1 or 2 times daily
(metformin XR)
Side effects
Diarrhea, nausea
Main risk
Lactic acidosis
Riddle MC. Am Fam Physician. 1999;60:2613-2620;
Cusi K et al. Diabetes Rev. 1998;6:89-131
α-Glucosidase Inhibitors
Acarbose and Miglitol
Mechanism of action
Delay carbohydrate
absorption
Efficacy depends upon
Postprandial hyperglycemia
Power
Decrease A1C 0.5%–1%
Dosing
3 times daily
Side effects
Flatulence
Main risk
Liver enzyme elevation (rare)
Riddle MC. Am Fam Physician. 1999;60:2613-2620;
Lebovitz HE. Endocrinol Metab Clin North Am. 1997;26:539-551
Glitazones (TZDs)
Pioglitazone and Rosiglitazone
Mechanism of action
Enhance tissue response to
Efficacy depends upon
insulin
Presence of insulin and resistance
to its action
Power
Decrease A1C 0.9%–1.6%
Dosing
Once daily
Side effects
Edema, weight gain, anemia
Main risk
Congestive heart failure
Riddle MC. Am Fam Physician. 1999;60:2613-2620; Zinman B. Diabetes Obesity
Metab. 2001;3(suppl 1):S34-S43; Actos (pioglitazone hydrochloride) package insert;
Avandia (rosiglitazone maleate) package insert
Antihyperglycemic Agents
Major Sites of Action
-Glucosidase inhibitors
Glitazones
–
Plasma glucose
Carbohydrate absorption
Glucose uptake
GI tract
Metformin
+
+
Glucose production
–
Liver
–
Insulin secretion
Secretagogues
+
Pancreas
Muscle/Fat
– Injected
insulin
+
Glucose Profiles in Type 2 Diabetes
Effects of Correcting
Basal vs Postprandial Hyperglycemia
Plasma
glucose
(mg/dL)
300
A1C 9%
A1C 7%
200
A1C 6%
100
Normal—A1C 5%
0800
1200
1800
Time of day
0800
Effects of Metformin Added to a Sulfonylurea
Glucose and Insulin Profiles
Glipizide alone
Glipizide + metformin
Glucose
Insulin
pmol/L 500
mg/d 300
400
L
200
300
200
100
100 Meal Meal
Meal Meal
0
0
0800
1200
1800
0800
2400
Time of day
Jeppesen J et al. Diabetes Care. 1994;17:1093-1099
1200
1800
2400
Oral Antihyperglycemic
Monotherapy
Maximum Therapeutic Effect on A1C
Nateglinide
Acarbose
Repaglinide
Rosiglitazone
Pioglitazone
Glimepiride
Glipizide GITS
Metformin
0
-0.5
-1.0
-1.5
Reduction in A1C (%)
Diabetes Care. 2000;23:202-207; Precose (acarbose) package insert; Drugs. 1995;50:263-288;
J Clin Endocrinol Metab. 2001;86:280-288; Diabetes Care. 2000;23:1605-1611; Diabetes Care. 1996;
19:849-856; Diabetes Care. 1997;20:597-606; Am J Med. 1997;102:491-497
-2.0
Treatment of Postprandial Glycemia
Conclusions From Studies

Most oral agents control mainly fasting
(basal) hyperglycemia

Acarbose, miglitol, and nateglinide have
the greatest effect on postprandial
increments and the least ability
to reduce A1C
Time Course of Action of
Oral Antihyperglycemics
Effect on Fasting Plasma Glucose
Rosiglitazone (8 mg) added to metformin
FPG
(mg/dL)
Metformin (up to 2550 mg)
Glimepiride (4 mg)
0
-20
-40
-60
0
2
4
8
12
Weeks of treatment
DeFronzo RA et al. N Engl J Med. 1995;333:541-549; Fonseca V et al.
JAMA. 2000;283:1695-1702; Goldberg RB et al. Diabetes Care. 1996;19:849-856
16
Selected Insulin Secretagogues
Dosing Information
Generic Name
Effect
Dose Strengths
Recommended Usual
Dose Range
Maximal
Glimepiride
1, 2, or 4 mg
1–8 mg
4 mg qd
Glipizide GITS
2.5, 5, or 10 mg
2.5–20 mg
5 or 10 mg qd
Glyburide
1.25, 2.5, or 5 mg
1.25–20 mg
5 or 10 mg bid
Nateglinide
60 or 120 mg
180–360 mg
120 mg tid
Repaglinide
0.5, 1, or 2 mg
1–16 mg
4 mg qid
Metformin, -Glucosidase Inhibitors,
Glitazones
Dosing Information
Generic Name
Effect
Dose Strengths
Recommended
Dose Range
Usual
Maximal
Metformin
500, 850, or
1000 mg
500 mg qd to
850 mg tid
1000 mg bid
Metformin XR
500 mg
500 mg qd to
1000 mg bid
1000 mg bid
Acarbose
25, 50, or 100 mg
25–100 mg tid
50 mg tid
Miglitol
25, 50, or 100 mg
25–100 mg tid
50 mg tid
Pioglitazone
15, 30, or 45 mg
15–45 mg qd
45 mg qd
Rosiglitazone
2, 4, or 8 mg
4–8 mg daily
4 mg bid
Metabolic Effects of
Oral Antihyperglycemics
Sulfonylureas
Meglitinides
Acarbose Pioglitazone
Miglitol Rosiglitazone
Metformin
Weight

 or 


LDL cholesterol



 or 
HDL cholesterol



 or 
Triglycerides



 or 
Medical Benefits
Substantiated in Published Clinical Trials
Microvascular
Cardiovascular
Insulin
Yes
Yes?
Sulfonylureas
Yes
No
Metformin
Yes
Yes?
-Glucosidase inhibitors
No
No
Glitazones (TZDs)
No
No
Repaglinide, nateglinide*
No
No
* Recently available agents with few trials documenting long-term outcomes
Severe Adverse Effects
Hypoglycemia
Insulin
Sulfonylureas
Metformin
-Glucosidase inhibitors
Glitazones (TZDs)
Repaglinide, nateglinide*
Yes
Yes
No
No
No
Yes
CV
No
No
No
No
Yes (CHF)
No
Lactic
acidosis
No
No
Yes
No
No
No
* Recently available agents with few trials documenting long-term outcomes
CV=cardiovascular; CHF=congestive heart failure
Efficacy of Oral Antihyperglycemics
Declines With Time

A1C rises at ~0.2% to 0.3% yearly on stable therapy

This rate is the same as for diet alone, sulfonylureas,
and metformin


-Cell function declines at the same rate with all
these treatments
Combination treatments are routinely needed
UKPDS Group. Diabetes. 1995;44:1249-1258; Turner RC et al. JAMA. 1999;281:2005-2012
Secondary Failure of Monotherapy
Overweight Patients in the UKPDS
Percent with A1C <7% on monotherapy
Diet
3 years
23
6 years
12
9 years
11
Sulfonylureas
45
28
21
Metformin
44
34
13
Turner RC et al. UKPDS 49. JAMA. 1999;281:2005-2012
Insulin Therapy

Who should be on
insulin?
 Insulin Deficient
 DKA
 Weight loss
 Patient on maximal
oral therapy

A1c not at goal
Insulin Therapy

Basal insulin plus
secretagogue



Lantus HS (10 units)
NPH HS (10 units)
Bolus and Basal

75/25


Novolog or Humalog
with NPH
70/30

Regular with NPH
New Therapies

Fat absorption blocker─orlistat (Xenical®)



Amylin analogue─pramlintide (Symlin™)



Oral intestinal lipase inhibitor
Approved for obesity, proposed for diabetes
Slows gastric emptying, suppresses glucagon, increases
satiety
Requires injection
GLP-1 analogues/agonists─exendin-4 (ByettaTM)



Potentiate insulin secretion, suppress glucagon
May promote -cell neogenesis
Require injection
GLP-1=glucagon-like peptide
Summary of
Oral Antihyperglycemic Agents





Four major classes of oral agents acting at different sites
are available
Fasting and preprandial glucose are reduced by
sulfonylureas, repaglinide, metformin, and glitazones
(TZDs), with lesser effects on postprandial increments
Postprandial glucose increments are reduced best by
-glucosidase inhibitors and nateglinide
A1C reductions are similar using sulfonylureas,
metformin, and glitazones
Secondary failure to monotherapy and oral therapies
routinely occurs
Complications of Diabetes
Type I and II

Atherosclerosis
Stroke
 Heart disease


Retinopathy


Leading cause of
blindness
Neuropathy
Peripheral
 Autonomic

 Nephropathy
Leading cause of end
stage renal disease
 One out of every 3
patients on dialysis or
transplant program

Risk of Progression of
Complications: DCCT Study
15
13
11
Relative
Risk
Diabetic retinopathy
Nephropathy
Neuropathy
Microalbuminuria
9
7
5
3
1
7
8
9
10
HbA1c %
11
12
Skyler JF. Endocrinol Metab Clin North Am. 1996;25:243-254.
Treatment of Diabetes

Treatment goals
Type I A1c < 7.0
 Type II A1c < 6.0



Minimize hypoglycemia
Maximize participation
in usual activities
Goals of Diabetes Treatment

Early detection of
complications:



Annual retinal exam
Annual renal exam
(microalbuminuria,
Creatinine)
Frequent lower extremity
examinations
Diabetes Management

Home blood glucose
monitoring


4 times daily
Periodically check at 3 AM



Office visit Q3-4
months


PM insulin
Every year



Monitor HgbA1c
Adjustment of
medication
Examine injection sites

TSH
Lipid panel



Hypertrophy
Lipoatrophy
Blood pressure
Weight
Conclusions

Type II Diabetes is
multifactorial



Therapy



Metabolic syndrome
Fatty acid excess
Multiple agents needed
With time insulin is needed
Tight control prevents
complications


Silent disease
Assume 10 years of disease
and vascular damage at time
of diagnosis
Conclusions

Therapy





Diet therapy
Exercise
Medical therapy




Multiple agents needed
With time insulin is needed
Insulin
Oral agents
Adjunctive therapies
Education


Diabetes Team
MD, RN CDE, Dietitian, Social
work and Psychiatry
Diet Therapy

Lose weight




Decrease portion size



1 pound per week
Decreased intake of 500-1000
calories per day
3500-7000 calories per week
Decrease carbohydrate intake
Lower fat intake
Increase activity

Walk the dog
you don’t have one)
(even if
Pramlintide Reduces A1C and Weight
Combination With Insulin for Type 2 Diabetes
Placebo + insulin
Pramlintide 150 g tid + insulin
 A1C %
 kg
A1C
Placebo-subtracted difference 0.4%
Weight
1.5
0
1.0
-0.2
0.5
*P<0.01
-0.4
*
*
-0.6
-0.8
*
0
13
26
0
-0.5
*
*P<0.01
-1.0
*
-1.0
*
Placebo-subtracted difference 2.5 kg
39
-1.5
52
0
Week
Ratner RE et al. Diabetes Technol Ther. 2002;4:51-61
*
*
13
26
*
39
52
Synthetic Exendin-4 Reduces A1C and Weight
28-Day Treatment of Type 2 Diabetes
109 Patients With Continued Treatment on Sulfonylurea, Metformin, or Both
Placebo
AC2993 bid
A1C
 A1C Placebo-subtracted difference -0.8%
% 0
-0.2
-0.3%
Placebo-subtracted difference -2.9 lb
 lb
3.0
2.0
-0.4
1.0
-0.6
P0.006
-0.8
-1.0
Weight
-1.1%
-1.2
0
-1.0
-2.0
Fineman MS et al. Diabetes 2002;51:A85
2.0
-0.9
Orlistat Reduces A1C and Weight
Treatment of Patients With Type 2
Diabetes
% body
weight
change 0
A1C (%)
9.0
8.5
-2
P=0.0003
8.0
P=0.006
-4
7.5
7.0
Placebo
Orlistat 120 mg tid
-4 0
12
24
-6
36 48
Week
Hanefeld M et al. Diabetes Obes Metab. 2002;4:415-423
-4 0
12
24
36 48
Insulin Action in Muscle and Fat Cells
Mobilization of GLUT4 to the Cell Surface
Plasma membrane
Insulin
receptor
Intracellular
signaling
cascades
Intracellular
GLUT4 vesicles
Insulin
GLUT4 vesicle mobilization
to plasma membrane
GLUT4 vesicle
integration into plasma
membrane
Glucose entry into cell
via GLUT4
GLUT4=glucose transporter 4