Diabetes Mellitus

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Diabetes Mellitus

• Sufyan Said, M.D.
• Staff Physician, CAVHS
• Assistant Professor, UAMS

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Definition of Diabetes Mellitus

• 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. 199821(suppl 1)S5-S19
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1998 Criteria for the Diagnosis of Diabetes
Mellitus

• (Each must be confirmed on a subsequent day.)
• Symptoms of Diabetes plus casual plasma
  glucose concentration ? 200mg/dl
• Or
• Fasting plasma glucose ? 126 mg/dl
• Or
• 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. 199821(suppl 1)S5-S19
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Estimated Prevalence (20- 79 age group)
Country Prevalence () Country Prevalence ()
Papua New Guinea 15.5 Aruba, Bermuda, British Virgin Islands, Cayman Islands, Grenada, Hong Kong, St Kitts, Nevis 12.1
Mauritius 15.0 Aruba, Bermuda, British Virgin Islands, Cayman Islands, Grenada, Hong Kong, St Kitts, Nevis 12.1
Bahrain 14.8 Aruba, Bermuda, British Virgin Islands, Cayman Islands, Grenada, Hong Kong, St Kitts, Nevis 12.1
Mexico 14.2 Aruba, Bermuda, British Virgin Islands, Cayman Islands, Grenada, Hong Kong, St Kitts, Nevis 12.1
Trinidad Tobago 14.1 Pakistan 11.8
Trinidad Tobago 14.1 Czech Republic 11.7
Barbados 13.2 Tonga 11.5
IDF D I A B E T E S 2000 executive summary page 10
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Incidence and Prevalence of 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, gt798,000 Americans develop diabetes
• gt2,200 each day

Harris MI et al. Diabetes Care. 199821518-524.
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Prevalence of Diabetes and Impaired Fasting
GlucoseUS, 1988-1994
Percent of Population
Age (yr)
Harris MI et al. Diabetes Care. 1998 21518-524.
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1997 Per Capita Health Care CostsPersons With
and Without Diabetes
25
23.5
Diabetes
No diabetes
20
15
12.2
Annual Cost (1000s)
10
5
2.5
1.5
0.7
0.7
0.7
0.4
0.4
0.2
0
Outpatient
Office
ER
Outpatient
Inpatient
Drugs
Visits
Services
Data from American Diabetes Association. Diabetes
Care. 199821296-309.
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History 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.

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History 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
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History 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.

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History 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.

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Comparison of clinical, genetic and immunologic
features 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 gt85 Rare
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Insulin Resistance Impaired b-Cell Function
Insulinresistance
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Visceral Fat DistributionNormal vs Type 2
Diabetes
Normal
Type 2 Diabetes
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Natural History of Type 2 Diabetes
Obesity IFG Diabetes Uncontrolled
hyperglycemia
Postmeal glucose
Fasting glucose
Glucose (mg/dL)
Insulin resistance
Relative function ()
Insulin level
?-cell failure
-10 -5 0 5 10 15 20 25 30
Years of diabetes
IFGimpaired fasting glucose.
Adapted from International Diabetes Center
(Minneapolis, Minn).
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Approach to Treatment of Type 2 Diabetes

• Diet
• Exercise
• Weight reduction
• Oral agents
• Insulin
• Careful attention to cardiovascular risk factors
  hypertension, smoking, dyslipidemia and family
  history

Diabetes Care. 199821(suppl 1)S23-S31
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Goals of Diet Therapy Metabolic Control and
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. 199821(suppl 1)S32-S35
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Antihyperglycemic AgentsMajor Sites of Action
Plasma glucose
GI tract
Muscle/Fat
Liver


Pancreas
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Pharmacological approaches to Treatment 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
• a-Glucosidase Inhibitors
• Acarbose Precose
• Miglitol Glycet
• Insulin
• Several

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The a-Glucosidase InhibitorsBasic
Characteristics of Acarbose and Miglitol

• Mechanism of action Delays carbohydrate
  absorption
• Depends upon Postprandial hyperglycemia
• Power Decreases HbA1c 0.5 to 1
• Dosing Three times daily
• Side effects Flatulence
• Main risk Liver enzyme elevation (rare)

Medical Management of Type 2 Diabetes. 4th ed.
Alexandria, Va American Diabetes Association
19981-139.
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The Thiazolidinediones (Glitazones)Basic
Characteristics of Glitazones

• Mechanism of action Enhance muscle and
  adipose tissue 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 daily
• Side effects Edema, weight gain, anemia
• Main risk Liver failure (? troglitazone only)

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The BiguanidesBasic Characteristics of Metformin

• Mechanism of action Decreases hepatic
  glucose production
• Depends upon Presence of insulin
• Power Decreases HbA1c 1 to 2
• Dosing One to three times daily
• Side effects Diarrhea, nausea
• Main risk Lactic acidosis

Data from Bell Hadden. Endocrinol Metab Clin.
199726523-537 De Fronzo, et al. N Engl J Med.
1995333541-549 Bailey Turner. N Engl J Med.
1996334574-579 Medical Management of Type 2
Diabetes. 4th ed. Alexandria, Va American
Diabetes Association 19981-139.
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The Insulin SecretagoguesBasic Characteristics
of the Sulfonylureas and the Meglitinides
Mechanism of action Increase basal and
postprandial insulin secretion Depends upon
Functioning ?-cells Power Decreases HbA1c 1 to
2 Dosing Once or twice daily (sulfonylureas) th
ree times daily (meglitinides) Side
effects Weight gain Main risk Hypoglycemia
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Practical Management of Type 2 Diabetes Mellitus
FBG gt126 mg/dL
Diet and Exercise
Monotherapy
126-140 mg/dL
140-200 mg/dL
200-240 mg/dL
240-300 mg/dL
gt300 mg/dL
Sulfonylurea Metformin Acarbose
Sx
No Sx
No Sx/Sx
Sx
No Sx
Acarbose
Repaglinide
Insulin
Sulfonylurea
Sulfonylurea
Sulfonylurea
Glitazones
Metformin
Sulfonylurea
Sulfonylurea
Metformin
Oral Combination
Triple Therapy

• Evolving criteria
• If FBG gt140 mg/dL (126 mg/dL)
• HbA1c gt8 (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

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Insulin Structure
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Insulin Preparations

• Class Agents
• Human insulins Regular, NPH, lente, ultralente
• Insulin analogues Aspart, glulisine, lispro,
  glargine
• Premixed insulins Human 70/30, 50/50
• Humalog mix 75/25
• Novolog mix 70/30

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Human Insulin
21 amino acids
A-chain
B-chain
30 amino acids
Monomers
Dimers
Self-aggregation in solution
Hexamers
Zn
Zn
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Modified Human Insulin
Regular Insulin Short acting Hexamers in Zn2
buffer Neutral Protamine Hagedorn (NPH)
Insulin Intermediate acting Medium-sized crystals
in protamine-Zn2 buffer Lente and Ultralente
Insulin Intermediate andLarge crystals in
acetate-Zn2 buffer long acting
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Insulin Analogues
Human Insulin Dimers and hexamers in solution
A-chain
B-chain
Aspart Limited self-aggregation Monomers in
solution
Asp
Glulisine Limited self-aggregation Monomers in
solution
Glu
Lys
Lispro Limited self-aggregation Monomers in
solution
Lys Pro
Gly
Glargine Soluble at low pH Precipitates
at neutral (subcutaneous) pH
Arg Arg
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Insulin Glargine
A-chain
S
S
Gly
Asn 21
Gly 1
Ile 2
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
Val 3
Glu 4
S
S
S
S
Cys 19
Glu 21
Arg 22
Gly 23
Phe 24
Phe 25
Tyr 26
Thr 27
Pro 28
Lys 29
Thr 30
Gly 20
Arg 31
Arg 32
Phe 1
Val 2
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
Asn 3
Gin 4
B-chain
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
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Insulin Glargine Absorption
Adapted with permission from Kramer W. Exp Clin
Endocrinol Diabetes.1999107(suppl 2) S52-S61.
Please see accompanying prescribing information
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Insulin Profiles
Rosenstock J. Clin Cornerstone. 2001450-61.
Please see accompanying prescribing information
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Comparison of Human Insulins and Analogues
Insulin Preparations
Onset of Action
Duration of Action
Peak

• 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.
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Moderate intensive therapy
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Intensive Therapy
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Insulin Pen
5-21
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1 Pump moves insulin...
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.
2 ...into the Subcutaneous tissue where it
eventually diffuses...
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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.
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Relationship of A1C to Risk of Microvascular
Complications
Retinopathy
15
Nephropathy
13
Neuropathy
Microalbuminuria
11
9
Relative Risk
7
5
3
1
6
7
8
9
10
11
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A1C ()
Based on DCCT data
Adapted with permission from Skyler JS.
Endocrinol Metab Clin North Am. 199625243
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DCCTMicrovascular Risk Reduction With Intensive
Treatment
Reduction inComplication Relative
Risk Retinopathy 63 Nephropathy 54 Neuropathy 6
0
Data from the Diabetes Control and Complications
Trial Research Group. N Engl J Med.
1993329977-986.
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Results of Intensive Glycemic Control in Type 2
Diabetes 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.
199528103-117
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Blood Glucose Control Guidelines
American Diabetes Association (ADA) American College of Endocrinology
Preprandial blood glucose 90-130 mg/dl lt110 mg/dl
Postprandial blood glucose lt180 mg/dl (peak) lt140 mg/dl (2 hour)
HBA1C lt7 lt6.5
American Diabetes Association. Diabetes Care.
2004 27(suppl 1)S1 .S150 American College of
Endocrinology. EndocrPract. 20028(suppl 1)40.82.
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lipoatrophy
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Cataract
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The End