diabetes mellitus sufyan said, m.d. staff physician, cavhs assistant professor, uams
TRANSCRIPT
Diabetes MellitusDiabetes Mellitus
Sufyan Said, M.D.Staff Physician, CAVHS
Assistant Professor, UAMS
Definition of Diabetes Definition of Diabetes MellitusMellitus
Diabetes Mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both
The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially in the eyes, kidneys, nerves, heart and blood vessels.
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.Diabetes Care. 1998;21(suppl 1):S5-S19
1998 Criteria for the Diagnosis of Diabetes 1998 Criteria for the Diagnosis of Diabetes MellitusMellitus
(Each must be confirmed on a subsequent day.) Symptoms of Diabetes* plus casual† plasma
glucose concentration 200mg/dlOr
Fasting plasma glucose‡ 126 mg/dlOr
2-h plasma glucose 200 mg/dl during an OGTT§
* Classic Symptoms = polyuria, polydipsia, and unexplained weight loss.† Casual = any time of the day without regard to time since last meal.‡ Fasting = no calori intake for at least 8 h.§ Requires use of a glucose (75 gm) load.OGTT = oral glucose tolerance test.The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.Diabetes Care. 1998;21(suppl 1):S5-S19
Estimated Prevalence (20- 79 age Estimated Prevalence (20- 79 age group)group)
Country Prevalence
(%)
Country Prevalence
(%)
Papua New Guinea
15.5 Aruba, Bermuda, British Virgin
Islands, Cayman Islands, Grenada,
Hong Kong, St Kitts, Nevis
12.1Mauritius 15.0
Bahrain 14.8
Mexico 14.2
Trinidad
Tobago
14.1 Pakistan 11.8
Czech Republic 11.7
Barbados 13.2 Tonga 11.5
IDF D I A B E T E S 2000 executive summary page 10
Harris MI et al. Diabetes Care. 1998;21:518-524.
Incidence and Prevalence of Incidence and Prevalence of Diabetes (US)Diabetes (US)
15.7 million Americans have diabetes
Nearly 6% of the population 5.4 million of these people are unaware
they have diabetes Each year, >798,000 Americans
develop diabetes
>2,200 each day
0
5
10
15
20
25
30
35
20-39 40-49 50-59 60-74 75+
Undiagnosed Diabetes
Diagnosed Diabetes
Impaired Fasting Glucose
Age (yr)
Per
cen
t of
Pop
ula
tion
Prevalence of Diabetes and Impaired Prevalence of Diabetes and Impaired Fasting GlucoseFasting GlucoseUS, 1988-1994US, 1988-1994
Harris MI et al. Diabetes Care. 1998; 21:518-524.
1997 Per Capita Health Care Costs:1997 Per Capita Health Care Costs:Persons With and Without DiabetesPersons With and Without Diabetes
Data from American Diabetes Association. Diabetes Care. 1998;21:296-309.
An
nu
al C
ost
($10
00s)
0
5
10
15
20
25
OutpatientDrugs
OfficeVisits
EROutpatientServices
Inpatient
23.5
12.2
2.51.5
0.7 0.4 0.7 0.4 0.7 0.2
Diabetes
No diabetes
History of DiabetesHistory of Diabetes
1500 BCEarly healers notice that ants are attracted to the urine of people with a mysterious emaciating disease.
150 The Greek physician Aretaeus of Cappodocia writes about diabetes, which he says "melts the flesh."
1000 Greek physicians prescribe exercise, preferably on horseback, to relieve excess urination.
History of DiabetesHistory of Diabetes
1869Paul Langerhans discovers islet cells in the pancreas.
1889 Mehring and Minkowski produce DM in dogs by removing the pancreas.
1921Banting and Best find a pancreatic extract that lowers blood glucose in pancreatectomized dogs.
VOL 101 / NO 4 / APRIL 1997 / POSTGRADUATE MEDICINE
History of DiabetesHistory of Diabetes
1923The Nobel Prize for medicine goes to Banting and Macleod for the discovery of insulin.
1950-1980DNA technology allows development of genetically engineered "human" insulin.
1980-1989Blood glucose self- management gives patients greater control and flexibility in managing diabetes.
History of DiabetesHistory of Diabetes
1990-1997More sophisticated insulin analogues are introduced, and multiple injections and insulin pumps offer promise of closer control.
2000 and beyondResearch continues for ways to cure both type 1 and type 2 diabetes.
Comparison of clinical, genetic and immunologic Comparison of clinical, genetic and immunologic features of type 1 and type 2 diabetesfeatures of type 1 and type 2 diabetes
Characteristic Type 1 Type 2
Onset Abrupt Progressive
Endogenous insulin Low to absent Normal, elevated or depressed
Ketosis Common Rare
Age at onset Any age Vast majority Adults
Body mass Usually non-obese Obese or nonobese
Family history 10-15% 30%
Twin concordance 30-50% 70-90%
HLA HLA-DR, HLA-DQ Unrelated
Autoantibodies >85% Rare
Insulin Resistance & Impaired Insulin Resistance & Impaired -Cell -Cell FunctionFunction
InsulinInsulinresistanceresistance
CompensatoryCompensatoryHyperinsulinemiaHyperinsulinemia
NormoglycemiaNormoglycemia
Normal Normal -cell -cell functionfunction
Relative insulin deficiencyRelative insulin deficiency
HyperglycemiaHyperglycemia
Type 2 diabetesType 2 diabetes
Abnormal Abnormal --cell functioncell function
Visceral Fat Distribution:Visceral Fat Distribution:Normal vs Type 2 DiabetesNormal vs Type 2 Diabetes
Normal Type 2 Diabetes
050
100150200250
Natural History of Type 2 Natural History of Type 2 DiabetesDiabetes
50100150200250300350
Obesity IFG* Diabetes Uncontrolled hyperglycemia
Postmeal glucose
Fasting glucose
Insulin resistance
Insulin level-cell failure
Glucose(mg/dL)
Relative function
(%)
Years of diabetes*IFG=impaired fasting glucose.
-10 -5 0 5 10 15 20 25 30
Adapted from International Diabetes Center (Minneapolis, Minn).
Approach to Treatment of Type 2 Approach to Treatment of Type 2 DiabetesDiabetes
Diet Exercise Weight reduction Oral agents Insulin Careful attention to cardiovascular risk
factors; hypertension, smoking, dyslipidemia and family history
Diabetes Care. 1998;21(suppl 1):S23-S31
Goals of Diet Therapy: Metabolic Control Goals of Diet Therapy: Metabolic Control and Balanceand Balance
Maintenance of as near-normal blood glucose levels as possible
Prevention of acute and long term complications of diabetes
Improvement of overall health through optimal nutrition Adequate calories for maintaining/attaining reasonable
weights for adults, normal growth and development in children and adolescents, increased metabolic needs during pregnancy and lactation, or recovery from catabolic illnesses
Diabetes Care. 1998;21(suppl 1):S32-S35
Antihyperglycemic Agents:Antihyperglycemic Agents:Major Sites of ActionMajor Sites of Action
Liver
Plasma glucose
GI tract
+
Pancreas
Muscle/Fat
–
Injected Insulin
(–)
(+)
-GlucosidaseInhibitors
(–)Carbohydrat
eAbsorption
Metformin (–)
GlucoseProduction
Glitazones
(+)Glucos
eUptake
InsulinSecretion
SulfonylureasMeglitinides
(+)Insulin
Secretion
Pharmacological approaches to Pharmacological approaches to Treatment of Type 2 DiabetesTreatment of Type 2 Diabetes
Sulfonylureas Glyburide Diabeta,
Micronase, Glynase Glipizide Glucotrol Glimepiride Amaryl
Meglitinides Neteglinide Starlix Rapeglinide Prandin
Biguanides Metformin Glucophage
Thiazolidinediones Pioglitazone Actos Rosiglitazone Avandia
α-Glucosidase Inhibitors
Acarbose Precose Miglitol Glycet
Insulin Several
The The -Glucosidase Inhibitors:-Glucosidase Inhibitors:Basic Characteristics of Acarbose and MiglitolBasic Characteristics of Acarbose and Miglitol
Mechanism of action Delays carbohydrate absorptionDepends upon Postprandial hyperglycemia
Power Decreases HbA1c 0.5% to 1%Dosing Three times dailySide effects FlatulenceMain risk Liver enzyme elevation (rare)
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.
The Thiazolidinediones The Thiazolidinediones (Glitazones):(Glitazones):
Basic Characteristics of GlitazonesBasic Characteristics of Glitazones
Mechanism of action Enhance muscle and adiposetissue response to insulin
Depends upon Presence of insulin and resistance to its action
Power Decreases HbA1c 0.5% to 1.5%Dosing Once or twice dailySide effects Edema, weight gain, anemia Main risk Liver failure (? troglitazone only)
The Biguanides:The Biguanides:Basic Characteristics of MetforminBasic Characteristics of Metformin
Data from Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537; De Fronzo, et al. N Engl J Med. 1995;333:541-549; Bailey & Turner. N Engl J Med. 1996;334:574-579; Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.
Mechanism of action Decreases hepatic glucoseproduction
Depends upon Presence of insulin
Power Decreases HbA1c 1% to 2%Dosing One to three times dailySide effects Diarrhea, nausea Main risk Lactic acidosis
The Insulin Secretagogues:The Insulin Secretagogues:Basic Characteristics of the Sulfonylureas and Basic Characteristics of the Sulfonylureas and
the Meglitinidesthe Meglitinides
Mechanism of action Increase basal and postprandialinsulin secretion
Depends upon Functioning -cells
Power Decreases HbA1c 1% to 2%
Dosing Once or twice daily (sulfonylureas);three times daily (meglitinides)
Side effects Weight gain
Main risk Hypoglycemia
Practical Management of Type 2 Diabetes Practical Management of Type 2 Diabetes MellitusMellitusFBG >126 mg/dL
Diet and Exercise
126-140 mg/dL 140-200 mg/dL 200-240 mg/dL 240-300 mg/dL >300 mg/dL
SulfonylureaMetforminAcarbose
Sx
Insulin
No Sx
Sulfonylurea
No Sx/Sx
Sulfonylurea
Evolving criteria If FBG >140 mg/dL (126 mg/dL) HbA1c >8% (7%?)
Add second oral agent and titrate to maximum dose
If no improvement: Try triple therapy? Or continue oral agent(s)
+ insulin Rx at PM or HS
Sx
Sulfonylurea
No Sx
SulfonylureaMetformin
Acarbose
Glitazones
Sulfonylurea
Repaglinide
Metformin
Oral Combination Triple Therapy
Monotherapy
Insulin StructureInsulin Structure
Insulin PreparationsInsulin PreparationsClass Agents
Human insulins Regular, NPH, lente,
ultralente
Insulin analogues Aspart, glulisine, lispro, glargine
Premixed insulins Human 70/30, 50/50Humalog mix 75/25Novolog mix 70/30
Human InsulinHuman InsulinA-chain
B-chain
Zn++
Zn++
Self-aggregationin solution
Monomers
Dimers
Hexamers
21 amino acids
30 amino acids
Modified Human InsulinModified Human Insulin
Regular Insulin Short actingHexamers in Zn2+ buffer
Neutral Protamine Hagedorn (NPH) Insulin Intermediate actingMedium-sized crystals in protamine-Zn2+ buffer
Lente and Ultralente Insulin Intermediate andLarge crystals in acetate-Zn2+ buffer long acting
Insulin AnaloguesInsulin AnaloguesHuman InsulinDimers and hexamers
in solution
A-chain
B-chain
Lys Pro
Gly
Arg Arg
Asp
LisproLimited self-aggregation
Monomers in solution
AspartLimited self-aggregation
Monomers in solution
GlargineSoluble at low pH
Precipitates atneutral (subcutaneous) pH
GluGlulisine
Limited self-aggregationMonomers in solution
Lys
Insulin GlargineInsulin GlargineA-chain
Phe
1
Val
2
Asn
3
Gin
4
His
5
Leu
6
Cys
7
Gly
8
Ser
9
His
10
Leu
11
Val
12
Glu
13
Ala
14
Leu
15
Tyr
16
Leu
17
Val
18
Cys
19
Glu
21
Arg
22
Gly
23
Phe
24
Phe
25
Tyr
26
Thr
27
Pro
28
Lys
29
Thr
30
Gly
20
Gly
1
Ile
2
Val
3
Glu
4
Gin
5
Cys
6
Cys
7
Thr
8
Ser
9
Ile
10
Cys
11
Ser
12
Leu
13
Tyr
14
Gin
15
Leu
16
Glu
17
Asn
18
Tyr
19
Cys
20
Asn
21
S
S S
S
S S
B-chain
Arg
31
Arg
32
GlyGly
Produced by recombinant DNA technology; 2 modifications in amino acid sequence of insulin molecule create stable molecule
Lantus® Prescribing Information. Please see accompanying prescribing information
Insulin Glargine: AbsorptionInsulin Glargine: Absorption
Clear Solution pH 4.0
pH 7.4
Precipitation
Dissolution
Capillary Membrane
Insulin in Blood
Hexamers Dimers Monomers
10-3 M 10-5M 10-8 M
Injection of an acidic solution (pH 4.0)
Precipitation of glargine in SC tissue (pH 7.4)
Slow dissolution of free glargine hexamers from precipitated glargine (stabilized aggregates)
Protracted action
Adapted with permission from Kramer W. Exp Clin Endocrinol Diabetes.1999;107(suppl 2): S52-S61.
Please see accompanying prescribing informationPlease see accompanying prescribing information
Insulin Profiles Insulin Profiles
Rosenstock J. Clin Cornerstone. 2001;4:50-61.Please see accompanying prescribing information
0 2 4 6 8 10 12 14 16 18 20 22 24
Pla
sm
a I
nsu
lin
Levels
Regular (6–10 hr)
NPH (10–20 hr)
Ultralente (~16–20 hr )
Time (hr)
Glargine (~24 hr)
Aspart, Lispro (4–5 hr)
Comparison of Human Insulins and Comparison of Human Insulins and AnaloguesAnalogues
Lispro/Aspart 5-15 minutes 1-2 hours 4-6 hours
Human Regular 30-60 minutes 2-4 hours 6-10 hours
Human NPH/Lente 1-2 hours 4-8 hours 10-20 hours
HumanUltralente 2-4 hours Unpredictable 16-20 hours
Glargine 1-2 hours Flat ~24 hours
The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only.
Insulin Preparations
Onset of Action Peak
Duration of Action
Moderate intensive therapyModerate intensive therapy
Intensive TherapyIntensive Therapy
Insulin PenInsulin Pen
5-21
1 Pump moves insulin...
2 ...into the Subcutaneous tissue
where it eventually diffuses...
3 ...to the Bloodstream, which slowly
carries the insulin...
4 ...to the Cells where it combines
with the insulin receptors, which
use it to allow glucose to enter
the cell and be metabolized.
GluControl® GC300 by Arthomed Last updated 8-2000 not FDA approved Uses Near-Infrared Quantitative Chemical Analysis.
SugarTrac® NONINVASIVE GLUCOSE MONITOR LifeTrac Systems, Inc. Uses Near-Infrared Quantitative Chemical Analysis. Clinical Trials being conducted in conjunction with Harvard University http://www.sugartrac.com
The Diasensor 2000 available in Europe Biocontrol Technology, Inc FDA is reviewing at this time Uses Near-Infrared Quantitative Chemical Analysis.
Relationship of A1C* to Risk of Microvascular Complications
Adapted with permission from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243
RetinopathyNephropathyNeuropathyMicroalbuminuria
Re
lati
ve
Ris
k
A1C (%)
15
13
11
9
7
5
3
16 7 8 9 10 11 12
*Based on DCCT data
DCCTDCCT
Microvascular Risk Reduction Microvascular Risk Reduction With Intensive TreatmentWith Intensive Treatment
Data from the Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.
Reduction inComplication Relative Risk
Retinopathy 63%
Nephropathy 54%
Neuropathy 60%
Results of Intensive Glycemic Control in Type 2 Results of Intensive Glycemic Control in Type 2 Diabetes: Kumamoto University StudyDiabetes: Kumamoto University Study
Intensive glycemic control reduced the risk of:
Retinopathy (65%) Severe retinopathy (40%) Worsening of nephropathy (70%) Microalbuminuria (57%)
Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117
Blood Glucose Control GuidelinesBlood Glucose Control Guidelines
American Diabetes Association (ADA)
American College of Endocrinology
Preprandial blood glucose
90-130 mg/dl <110 mg/dl
Postprandial blood glucose
<180 mg/dl (peak) <140 mg/dl (2 hour)
HBA1C <7 <6.5
American Diabetes Association. Diabetes Care. 2004; 27(suppl 1):S1 .S150American College of Endocrinology. EndocrPract. 2002;8(suppl 1):40.82.
lipoatrophylipoatrophy
CataractCataract
The EndThe End