TYPE 2 DIABETES MELLITUS

1
TYPE 2 DIABETES MELLITUS

• Richard Sachson MD

2
Diabetes in the U.S.
Diabetes and Gestational Diabetes Trends Among
Adults in the U.S., BRFSS 1990, 1995 and 2000
1990
1995
2000
4-6
gt 6
N/A
lt 4
incidence of diabetes among adults


Source Mokdad et al., Diabetes Care
2000231278-83 J Am Med Assoc 2001286(10).
3
DIABETES AND GESTATIONAL DIABETES AMONG ADULTS IN
THE U.S. -2001
4
Global Projections for Diabetes 19952010
26.5 32.9 24
14.2 17.5 23
84.5 132.3 57
9.4 14.1 50
15.6 22.5 44
1.0 1.3 33
World 2000 151 million 2010 221
million Increase 46
Reprinted with permission from Zimmet P et al.
Nature. 2001414782787.
5
Diabetes and Obesity The Continuing Epidemic
7.5
78

• Prevalence of obesityincreased by 61since 1991
• More than 50 of US adults are overweight
• Only 43 of obesepersons advised to loseweight
  during checkups
• BMI and weight gain majorrisk factors for
  diabetes

Diabetes
7.0
77
Mean Body Weight
6.5
76
6.0
Prevalence ()
kg
75
5.5
74
5.0
73
4.5
72
4.0
1990
1992
1994
1996
1998
2000
Year
BMI body mass index.Mokdad AH et al. Diabetes
Care. 2000231278-1283 Mokdad AH et al. JAMA.
19992821519-1522 Mokdad AH et al. JAMA.
20012861195-1200.
6
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7
Pathophysiology of Type 2 Diabetes
100
75
Defective ?-Cell Secretion
Pancreas
b-Cell Function ()
50
N 376
25
0
10
6
2
2
6
Years After Diagnosis
FFAs
Muscle
Liver
Insulin Resistance
Excess Glucose Production
ReducedGlucose Uptake
Fat
Fasting Hyperglycemia
Postprandial Hyperglycemia
FFAs free fatty acids.Adapted from UK
Prospective Diabetes Study Group. Diabetes.
1995441249-1258. DeFronzo RA. Diabetes.
198837667-687.
8
Progression of Type 2 Diabetes
9
Diabetes 16 Million and Climbing

• Estimated 10.3 million diagnosed 5.4 million
  undiagnosed cases
• Type 2 diabetes accounts for 90-95 of cases

60
12
17
8
Diagnosed Cases (Millions)
4
0
1980
1990
2000 (Estimated)
From Centers for Disease Control and Prevention,
2000.
10
Insulin Resistance

• FFA production

• Glucose production

Hyperinsulinemia
Dyslipidemia

• SNS activity

Abnormal Na handling
T2D
HTN
Atherosclerosis
11
ACANTHOSIS NIGRICANS
12
ACANTHOSIS NIGRICANS
13
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14
Metabolic Syndrome

• Also known as dysmetabolic syndrome, insulin
  resistance syndrome, syndrome X, the deadly
  quartet
• Prevalence in the United States approximately 47
  million
• Defined by having ? 3 of the following
• Abdominal obesity waist gt 40" (men) gt 35"
  (women)
• TG ? 150 mg/dL
• HDL lt 40 mg/dL (men) lt 50 mg/dL (women)
• Blood pressure ? 130/85 mm Hg
• FPG ? 110 mg/dL
• New ICD-9-CM code for dysmetabolic syndrome X is
  277.7

TG triglycerides FPG fasting plasma
glucose. Ford ES et al. JAMA. 2002287356-359. JA
MA. 20012852486-2497. American Association of
Clinical Endocrinologists. New ICD-9-CM code for
dysmetabolic syndrome X. Available at
http//www.aace.com/members/socio/syndromex.php.
Accessed January 10, 2002.
15
Visceral Fat DistributionNormal vs Type 2
Diabetes
Normal
Type 2 Diabetes
2-11
16
Prevalence of Complicationsat Time of Diagnosis
UKPDS

• Complication Prevalence ()
• Any complication 50
• Retinopathy 21
• Abnormal ECG 18
• Absent foot pulses (? 2) and/or ischemic
  feet 14
• Impaired reflexes and/or decreased vibration
  sense 7
• Myocardial infarction/angina/claudication 2-3
• Stroke/transient ischemic attack 1

Some patients had more than 1 complication at
diagnosis. Prevalence of each individual
condition. UKPDS United Kingdom Prospective
Diabetes Study. UKPDS Group. Diabetologia.
199134877-890.
17
Cardiovascular Disease and Diabetes

• Cardiovascular disease affects 80 of those
  with diabetes
• Accounts for 70 of mortality
• 75 of hospital stays in diabetes are for CVD
  complications
• Up to 50 of newly diagnosed patients with Type 2
  diabetes have established CVD
• CVD related health care costs 70 billion/year

National Diabetes Data Group. Diabetes in
America. 2nd ed. NIH1995.
18
Cardiovascular Disease and Diabetes

• 2-4 times more likely to die of coronary artery
  disease compared with non-diabetics
• 4 times as likely to develop peripheral vascular
  disease
• 2-4 times more likely to suffer a stroke
• Minority populations face even a greater risk of
  diabetes and its complications

19
Adult Treatment Panel III (ATP III) Guidelines

• National Cholesterol Education Program

20
Diabetes

• In ATP III, diabetes is regarded as a CHD risk
  equivalent.

21
Type 2 diabetes and CHD 7-year incidence of
fatal/nonfatal MI (East West Study)
Nondiabetic Diabetic n 1373 n 1059
50
45
45
P lt 0.001
P lt 0.001
40
35
30
7-year incidence rate of MI
25
20
19
20
15
10
4
5
0
No prior MI MI No prior MI MI
MI myocardial infarction. These patients had
no prior MI at baseline. Haffner SM, et al. N
Engl J Med. 1998339229234.
22
Target Lipid Levels forAdult Patients with
Diabetes
lt 100 mg/dL (high risk lt 70 mg/dl)
LDL Cholesterol
Men gt 45 mg/dL Women gt 55 mg/dL
HDL Cholesterol
lt 150 mg/dL
Triglycerides
Note The recent NCEP/ATP III guidelines suggest
that in patients with triglycerides ? 200 mg/dL,
the non-HDL cholesterol be calculated with a
goal being lt 130. American Diabetes Association.
Diabetes Care. 200225S33.
23
Recommended Treatment Goals for Hypertension for
Adults With Diabetes

• Target BP
• Patients aged ?18 years lt130/80 mm Hg
• Isolated systolic hypertension
• ?180 mm Hg lt160 mm Hg160179 mm Hg ? of 20 mm
  Hg

American Diabetes Association. Diabetes Care.
200124(suppl 1)S33-S43.
24
Aspirin

• Use aspirin therapy ( 75-325 mg/day ) in all
  adult patients with diabetes and macrovascular
  disease.
• Consider aspirin therapy for primary prevention
  in patients over age 40 with diabetes and one or
  more other CV risk factors ( including obesity ).
• Also consider patients between age 30-40.

25
Type 2 Diabetes Prevention
26
Finnish Diabetes Prevention Program

• 522 patients with IGT
• Age 40-65 years
• Mean BMI 31 kg/m2
• Intervention diet and exercise
• Mean duration of follow up 3.2 years

IGT impaired glucose tolerance BMI body mass
index. Tuomilehto J et al. N Engl J Med.
20013441343-1350.
27
The Finnish Diabetes Prevention Study Lifestyle
Modifications
2-Hour PPG
FPG
Incidence of Diabetes (Cases/1000 Person-Years)
Change from Baseline (mg/dL)

• 58
• P lt .001

P lt .001
P lt .003
Control Intervention (Diet and Exercise)
FPG fasting plasma glucose PPG postprandial
glucose. Tuomilehto J et al. N Engl J Med.
20013441343-1350.
28
Finnish DPP Results
Quintile Weight Change () Risk Reduction
() 1 ?11 ?83 2 ?5 ?61 3 ?2 ?13 4 No
change No change 5 ?3 ?218
Each 3-kg weight loss doubles the benefit.DPP
diabetes prevention program.Tuomilehto J et al.
N Engl J Med. 20013441343-1350.
29
United States Diabetes Prevention Program

• 3234 patients with IGT
• 32.3 male 67.7 female
• Mean age 50.6 years 10.7 years
• 55 Caucasian, 20 African American, 16
  Hispanic, 9 Asian and American Indian
• Interventions diet (reduced calorie, 25 fat)
  and exercise ( 150 minutes/week physical
  activity) or metformin (850 mg b.i.d.)
• Average follow-up 2.8 years (range 1.8-4.6
  years)

IGT impaired glucose tolerance. Diabetes
Prevention Program Research Group. N Engl J Med.
2002346393-403.
30
United States Diabetes Prevention Program Results
Intensive Lifestyle Placebo Intervention
Metformin (n 1082) (n 1079) (n 1073) Wt
loss 0.1 kg Wt loss 5.6 kg Wt loss 2.1
kg Diabetes 29 Diabetes 14 Diabetes
22
Average Cumulative incidence at 3
years. Diabetes Prevention Program Research
Group. N Engl J Med. 2002346393-403.
31
United States Diabetes Prevention Program Results
Intensive Lifestyle Placebo Intervention
Metformin (n 1082) (n 1079) (n 1073) Wt
loss 0.1 kg Wt loss 5.6 kg Wt loss 2.1
kg Diabetes 29 Diabetes 14 Diabetes
22 Risk reduction Risk reduction 58 31
Average Cumulative incidence at 3
years. Diabetes Prevention Program Research
Group. N Engl J Med. 2002346393-403.
32
United States Diabetes Prevention Program Notes

• Treatment effects did not differ significantly
  according to sex or to race or ethnic group
• No benefit seen with metformin in patients 60
  years of age or if BMI lt 30
• Metformin as effective as intensive lifestyle if
  44 years of age or BMI 35
• To prevent 1 case of diabetes during a period of
  3 years, 6.9 persons would have to receive
  intensive lifestyle intervention, and 13.9 would
  have to receive metformin

BMI body mass index.Diabetes Prevention
Program Research Group. N Engl J Med.
2002346393-403.
33
Diabetes Prevention TRIPODTroglitazone in
prevention of diabetes
34
Risk of Type 2 Diabetes in Women with History of
GDM

• Risk for Type 2 diabetes in women with history of
  GDM is 14.3 per year
• This varies depending on ethnic origin and
  glycemic status in the postpartum period
• In Latino women, 50 progress to type 2 diabetes
  within 5 years
• If glucose intolerance remains in the post-partum
  period, the risk increases to 70-80 within 5
  years
• Buchanan, TA. Diabetes. 2000. 49782.

35
TRIPOD Troglitazone in Prevention of Diabetes

• Single-center, randomized placebo-controlled,
  double-masked study
• Primary aim test the hypothesis that a reduction
  in secretory demands placed on beta cells by
  chronic insulin resistance can prevent type 2
  diabetes in Hispanic women with recent
  gestational diabetes.
• Study population
• History of GDM in prior 4 years
• OGTT in the non-diabetic range but consistent
  with 70 risk of diabetes within 5 years
• Study intervention
• troglitazone 400 mg qd (n114) or placebo (n121)
• Median follow-up period 30 months
• TA Buchanan. 2001. JCEM. 86989. TA Buchanan et
  al. 2001. Diabetes 50 (S1) A81

36
TRIPOD Troglitazone in Prevention of Diabetes

• Annual incidence of Type 2 diabetes
• Troglitazone 5.4
• placebo 12.3 (p0.001)
• 56 reduction in the incidence of type 2 diabetes
• Women who did not develop diabetes are being
  retested 8 mo. after discontinuing troglitazone
• Baseline data predict that 10 (37) will develop
  diabetes if troglitazone simply "masked" diabetes
• Of 27 of 55 tested to date, 1 developed diabetes
  (4, plt0.05) despite return of Si to pre-trial
  levels
• TA Buchanan. 2001. Diabetes Care, 50 (S2) A81.

37
Prevention of Diabetes with Ramipril HOPE Trial
0.10 0.08 0.06 0.04 0.02 0.00
Placebo (n 2883) Ramipril (n 2837)
RRR 34 (P lt .001)
Cumulative Risk
400
800
1200
1600
Days of Follow-Up
HOPE Heart Outcomes Prevention Evaluation.RRR
relative risk reduction. Yusuf S et al. JAMA.
20012861882-1885.
38
Prevention of Diabetes with Pravastatin WOSCOPS
6
Placebo (n 2975) Pravastatin (n 2999)
4
RRR 30 (P .036)
(n 82)
New Diabetes ()
2
(n 57)
0
0
1
2
3
4
5
Years in Study
Number of persons in study who developed
diabetes.WOSCOPS West of Scotland Coronary
Prevention Study. RRR relative risk
reduction. Freeman DJ et al. Circulation.
2001103357-362.
39
Diabetes Prevention with Pharmacologic Therapy
Ongoing Trials

• EDIT (multinational)
• Placebo, acarbose, or metformin
• First results expected in 2002
• DREAM (United States, Canada, and Europe)
• Placebo, rosiglitazone, ramipril, or combination
• Completion expected in 2005
• NAVIGATOR (30 countries)
• Placebo, nateglinide, valsartan, or combination
• Recruitment started in 2001

Diabetes Trials Unit. Early diabetes prevention
trial (EDIT). Available at http//www.dtu.ox.ac.
uk/index.html?maindoc/edit/design.html. Accessed
January 29, 2002. Gentiva Health Services.
Largest prevention trial to date launched.
Available at http//www.gentiva.com/consumer/diab
etes/diabetes_lib.asp. Accessed January 29,
2002.Gerstein HC et al. DREAM Trial (diabetes
reduction approaches with medication) summary.
Available at http//www.ccc.mcmaster.ca/projects/
dream/dream.htm. Accessed January 29, 2002.
40
TREATMENT OF TYPE 2 DIABETES
41
Therapy for Type 2 Diabetes Sites of Action
42
Sulfonylureas
43
Sulfonylurea Effects on the ?-cell
Ca
VDCC
()
Depolarization
?-Cell
KATP Channel
Free Ca
K
SUR
Metabolism
Sulfonylurea
Insulin Release
Glucose
Hu S et al. J Pharmacol Exp Ther 200029344452
44
Sulfonylureas

• Mechanism of action increases pancreatic insulin
  secretion
• Reported A1C reduction 0.9-2.5
• Advantages well-established, decreases
  microvascular risk, convenient daily dosing
• Disadvantages hypoglycemia, weight gain,
  hyperinsulinemia (role uncertain)
• FDA approval status monotherapy combination
  with insulin, metformin, thiazolidinedione,
  ?-glucosidase inhibitors

Inzucchi SE. JAMA. 2002287360-372.
45
Second-Generation Sulfonylureas
Duration of Action
Daily Dosage (mg)
Trade Names
Drug
16-24 hours
2.5-20
Micronase, DiaBeta, Glynase
Glyburide
12-24 hours
5-40
Glucotrol
Glipizide
24 hours
5-20
Glucotrol XL
16-24 hours
1-8
Amaryl
Glimepiride
The maximally effective dosage is 20 mg/d,
although it is approved for dosages ? 40
mg/d.DeFronzo RA. Ann Intern Med.
1999131281-303.
46
Nonsulfonylurea Secretagogues
47
Nonsulfonylurea Secretagogues (Repaglinide or
Nateglinide)

• Mechanism of action increases pancreaticinsulin
  secretion
• Reported A1C reduction 0.6-1.9
• Advantages targets postprandial glycemia,
  possibly less hypoglycemia and weight gain than
  with sulfonylureas
• Disadvantages 3-times daily dosing,
  hypoglycemia, weight gain, no long-term data,
  hyperinsulinemia (role uncertain)
• FDA approval status monotherapy combination
  with metformin

Inzucchi SE. JAMA. 2002287360-372.
48
Nonsulfonylurea Secretagogues
Daily Dosage (mg)
Trade Names
Drug
1.5-16
Prandin
Repaglinide
180-360
Starlix
Nateglinide
DeFronzo RA. Ann Intern Med. 1999131281-303. Sta
rlix package insert. East Hanover, NJ
Novartis Pharmaceuticals Corporation 2000.
49
ATP Sensitive K Channels
Kir
Type of Cell
SUR Receptor (ATP-Binding Cassette Superfamily)
Pancreatic b, neuronal Cardiac muscle, skeletal
muscle Smooth muscle
Kir 6.2 Kir 6.2 Kir 6.2
SUR 1 SUR 2A SUR 2B
From Lebovitz HE. Diabetes Rev.
19997139-153. Ashcroft FM, Gribble FM.
Diabetologia. 199942903-919.
50
How Does Glucose Stimulate Insulin Release?
From Aguilar-Bryan L, Bryan J. Diabetes Rev.
19964336-346. Ashcroft FM, Gribble FM.
Diabetologia. 199942903-919.
51
KATP Channel Open
ATP
Sulfonylurea-binding site
Voltage-dependentCa channel closed

K
ATP-bindingsite

Ca

K
ATP-sensitive K channel
Kir 6.2
From Ashcroft FM, Gribble FM. Diabetologia.
199942903-909. Berne R, Levy M. Physiology.
Chapter 46851-875.
52
KATP Channel Closed
ATP
Sulfonylurea
ATP
ADP
ATP
ATP

K
ATP
Exocytosis of insulin-containing granules
ATP-sensitive K channel closed
KIR 6.2
depolarization
From Ashcroft FM, Gribble FM. Diabetologia.
199942903-919. Bryan J, Aguilar-Bryan L.
Biochemica et Biophysica Acta. 19991461285-303.
Berne R, Levy M. Physiology. Chapter 46851-875.
53
Biguanides
54
Biguanides (Metformin)

• Mechanism of action decreased hepatic glucose
  production
• Reported A1C reduction 0.8-3.0
• Advantages well established, weight loss, no
  hypoglycemia, decreases microvascular risk,
  decreases macrovascular risk, nonglycemic
  benefits (decreased lipid levels, increased
  fibrinolysis, decreased hyperinsulinemia),
  convenient daily dosing
• Disadvantages adverse gastrointestinal effects,
  many contraindications, lactic acidosis (rare)
• FDA approval status monotherapy combination
  with insulin, sulfonylurea, nonsulfonylurea
  secretagogue, thiazolidinedione

Inzucchi SE. JAMA. 2002287360-372.
55
Metformin (Glucophage)

• Usual starting dose is 500 mg b.i.d. or 850 mg
  q.d. given with meals
• Dosage increases should be made in increments of
  500 mg weekly or 850 mg every 2 weeks up to 2000
  mg q.d.
• Maximum daily dose of 2550 mg per day
• doses gt 2000 mg may be better tolerated given
  t.i.d. with meals
• Contraindications renal disease or renal
  dysfunction, congestive heart failure requiring
  pharmacologic treatment, known hypersensitivity
  to the drug, acute or chronic metabolic acidosis,
  including diabetic ketoacidosis with or without
  coma, temporarily discontinue in patients
  undergoing radiologic studies involving
  intravascular administration of iodinated
  contrast materials
• Warning if lactic acidosis is suspected, the
  drug should be discontinued immediately and
  general supportive measures promptly instituted
• Precautions monitoring of renal function,
  hypoxic states, surgical procedures, alcohol
  intake, impaired hepatic function, vitamin B12
  levels, change in clinical status, hypoglycemia,
  loss of control of blood glucose
• Pregnancy category B

Serum creatine levels 1.5 mg/dL in males,
1.4 mg/dL in females.Glucophage package
insert. Princeton, NJ Bristol-Myers Squibb
Company 2000.
56
Glucophage XRGelShield Diffusion System

• Provides a controlled release of metformin

• Extends drug delivery over 24 hours

• Eases absorption through the gastrointestinal
  tract

Data on File. Bristol-Myers Squibb
Company. GelShield Diffusion System is a
trademark of Lipha s.a. licensed to Bristol-Myers
Squibb Company.
Please see full prescribing information,
including boxed WARNING regarding Lactic Acidosis.
57
Thiazolidinediones
58
Thiazolidinediones - Pharmacologic Actions

• Increase GLUT-4, PI-3K
• Oppose TNFa
• Lower FFA
• Reduce muscle TG, PKC

Reduce IR improve glycemic control

• Reduce ET-1 PAI-1 secretion
• Improve endothelial function
• Block VSMC proliferation
• Attenuate macrophage MMP-9 cytokine action

Cardiovascular protection
TZD
PPARg

• Islet insulin raised
• Reduce islet TG
• Reduce gluco- andlipotoxicity

b-cell protection
59
Thiazolidinediones

• Mechanism of action increased peripheral glucose
  disposal
• Reported A1C reduction 1.5-1.6
• Advantages reverses one of the primary defects
  of type 2 diabetes, no hypoglycemia, nonglycemic
  benefits (decreased lipid levels, increased
  fibrinolysis, decreased hyperinsulinemia,
  improved endothelial function), possible
  beta-cell preservation, convenient daily dosing
• Disadvantages liver function test monitoring,
  weight gain, edema, slow onset of action, no
  long-term data
• FDA approval status monotherapy combination
  with insulin , sulfonylurea, metformin

Inzucchi SE. JAMA. 2002287360-372.
60
Thiazolidinediones
DeFronzo RA. Ann Intern Med. 1999131281-303.
61
a-Glucosidase Inhibitors
62
a-Glucosidase Inhibitors

• Mechanism of action decreased gut carbohydrate
  absorption
• Reported A1C reduction 0.4-1.3
• Advantages targets postprandial glycemia, no
  hypoglycemia, nonsystemic
• Disadvantages t.i.d. dosing, adverse
  gastrointestinal effects, no long-term data
• Miglitol FDA approval status monotherapy
  combination with sulfonylurea
• Acarbose FDA approval status monotherapy
  combination with sulfonylurea, insulin, and
  metformin

Inzucchi SE. JAMA. 2002287360-372.
63
a-Glucosidase Inhibitors
Daily Dosage (mg)
Trade Names
Drug
25 q.d. to 50-75 t.i.d.
Precose
Acarbose
25 t.i.d. to 100 t.i.d.
Glyset
Miglitol
DeFronzo RA. Ann Intern Med. 1999131281-303.
64
Combination Therapy
65
Synergistic Mechanisms of Action of Glyburide
and Metformin

Enhances Insulin Secretion
Glyburide/
Metformin

• Decreases Insulin Resistance
• Increases peripheral glucose uptake
• Decreases hepatic glucose production
• Decreases intestinal absorption of glucose

Improves Glycemic Control
66
Distribution of Glyburide Particle Sizes in
Glucovance Tablets
Composed of a Spectrum of Glyburide Particle Sizes
Glucovance Product Labeling. Bristol-Myers Squibb
Company.
Please see full prescribing information,
including boxed WARNING regarding Lactic Acidosis.
67
Glucovance vs MetforminGlyburide in Type 2
Diabetes
Treatment
N 35 35 AUC(0-3) 95 47 Ratio 2.005
(plt0.001) AUC(0-T) 431 433 Ratio 0.995
(p0.919)
2
0
4
8
12
6
10

• Glucovance delivers twice as much glyburide over
  the first 3 hours when given with a meal

Donahue SR, et al. Endocrine Practice. 20028149.
Please see full prescribing information,
including boxed WARNING regarding Lactic Acidosis.
68
Complementary Mechanisms of Action

Metaglip (glipizide and metformin HCl) tablets

• Glipizide
• Enhances insulin secretion

• Metformin
• Improves insulin sensitivity by increasing
  peripheral glucose uptake
• Decreases hepatic glucose production
• Decreases intestinal absorption of glucose

Improves Glycemic Control
Please see full prescribing information,
including boxed WARNING regarding Lactic Acidosis.
69
AvandametAvandia Metformin
70
Basic Steps in the Management of Type 2 Diabetes
insulin
Oral plus Insulin
Oral combination
Oral monotherapy
diet exercise
71
Insulin

• Advantages
• Can control all patients
• Used to overcome glucose toxicity
• Flexibility in dosing
• Multiple insulin preparations available
• Use during pregnancy

• Disadvantages
• Hypoglycemia
• Weight gain
• Parenteral administration

DeFronzo. Ann Intern Med. 1999131281303.
72
Insulins for Type 2 Diabetes
72
73
Pre-Mixed Insulin Analogs

• Humalog Mix75/25
• Novolog mix 70/30

73
74
Why NPL Was Developed
R
L

R
L
R
NPH
L

NPL
74
75
Premix Insulin Profiles
Insulin aspart
Human regular
30
30
Neutral Protamine Hagedorn (NPH)
Insulin aspart protamine suspension
70
70
Human Premixed 70/30
NovoLog Mix 70/30
76
NPL Component Compared to Human NPH
8
Human NPH (0.4 U/kg)
7
NPL Component (0.4 U/kg)
6
5
n8 Non-diabetic Subjects
4
Glucose Infusion Rate
mg/min/kg
3
2
1
0
Hours After Injection
76
77
Lispro Mix75/25 Pharmacodynamics
Lispro Lispro Mix75/25 NPL
Glucose Infusion Rate mg/kg/min
0
4
8
12
16
20
24
Hours
Heise T, et al. Diabetes Care. 199821800-803.
78
Recommended Dosing

• Weight (kg) x units/kg total daily dose

Dosing Guidelines 0.20.5 for nonobese
individuals 0.4 0.8 for obese
individuals Obese BMI over 30Kgm
1 kg 2.2 lbs
79
GLP-1
80
GLP-1 Modes of Action in Humans

• Stimulates glucose-dependent insulin secretion

• Suppresses glucagon secretion

• Slows gastric emptying

GLP-1 is secreted from the L-cells in the
intestine

• Reduces food intake

• Improves insulin sensitivity

Long term effectsdemonstrated in animals
This in turn

• Increases beta-cell mass and maintains
  beta-cell efficiency

Drucker DJ. Curr Pharm Des 2001
71399-1412Drucker DJ. Mol Endocrinol 2003
17161-171
81
Exendin-4 in the Gila Monster

• Exendin-4 was originallyisolated from
  thesalivary secretions ofthe Gila monster
• Exendin-4 wassubsequently found tocirculate as
  a meal-related peptide in this animal
• Exendin-4 has possibleendocrine function in
  thelizard Heloderma suspectum(Gila monster)

400000
300000
Plasma Exendin-4 Concentration (pg/mL)
200000
100000
0
0
3
6
9
12
Time After Meal (h)
Data from Young AA. Glucagon-like peptide-1,
exendin and insulin sensitivity. In Hansen B,
Shafrir E, Editors. Insulin Resistance and
Insulin Resistance Syndrome. 1st ed. Harwood
Academic Press 2002, 235-262
82
DIET
83
Silverware for dieting
84
Questions
85
ACANTHOSIS NIGRICANS
86
ACANTHOSIS NIGRICANS
87
ACANTHOSIS NIGRICANS