1. Diabetes Mellitus: The Silent Epidemic
Epidemiology, Pathophysiology:Current
Concepts and Management strategies
Valentine J. Burroughs MD, MBA, CHCQM
Chief Medical Officer East Orange General Hospital
Newark Marriott Hotel
April 18, 2015

2. I have no commercial interests to
declare.

3. Undiagnosed diabetes
7 million
Prevalence of Glycemic Abnormalities
in the United States
Additional
79 million
with IGT = pre-diabetes
35% > 20 y.o.
50% > 65 y.o.
Diagnosed
type 2 diabetes
17.9 million
11.3% > 20y.o.; 25%>65y.o
Diagnosed
type 1 diabetes
~1.0 million
Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm;
Harris MI. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md:
NIDDK; 1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001
US Population: 375 Million in 2010 26 Million have Diabetes (8.3%);40% will
have diabetes during their lifetime; 50% of minorities during lifetime
10

4. Who Should Be Tested for Diabetes?
Consider if One or More of the Following Apply
• Symptoms suggesting diabetes: weight loss, hunger,
urinary frequency, blurred vision
• Age >45 (>30 if patient has other risk factors)
• Prior IGT or IFG or family history of diabetes
• Prior gestational diabetes or baby weighing >9 lb
• Women with polycystic ovarian syndrome (PCOS)
• Obesity (BMI 25 kg/m2), especially adolescents
• African, Latino, Asian, or Native American ancestry
• History of vascular disease or hypertension
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S11-S14;
AACE/ACE medical guidelines. Endocr Pract. 2002;8(suppl 1):40-82 19

5. Pancreatic Islet Cell Anatomy

7. Amino Acid Sequence and Covalent Structure of
Human Proinsulin

14. Glucose entry
GLUT2 glucose
transporter
Glucokinase
ADP/ATP
Potassium (KATP) channel
K+
Ca2+
Calcium channel
SUR 1
Insulin Secretion by the -Cell
Roles of Glucose, K+, and Ca2+
Glucose metabolism
ADP/ATP
K+
K+
Ca2+
Ca2+
Kir 6.2
Insulin secretory granules
opens
Ca2+
Ca2+
Insulin secretion
K+
KATP channel subunits:
SUR 1=regulatory subunit;
Kir 6.2=inward rectifying channel
closes

15. Insulin
receptor
Plasma membrane
GLUT4 vesicle mobilization
to plasma membrane
Insulin
Intracellular
signaling
cascades
Insulin Action in Muscle and Fat Cells
Mobilization of GLUT4 to the Cell Surface
GLUT4 vesicle integration
into plasma membrane
Glucose entry into cell
via GLUT4
Intracellular
GLUT4 vesicles
GLUT4=glucose transporter 4

16. Hyperglycemia
The Defining Feature of Diabetes
Hyperglycemia
Excessive
glucose production
Impaired
glucose clearance
Tissue injury
1

17. Normal Regulation of Plasma Glucose
Hepatic
insulin response
Muscle/fat
insulin response
Controlled
glucose production
Controlled
glucose clearance
Insulin
secretion
Normal
plasma glucose
12
Glucose enters
peripheral tissues
Glucose enters
the blood

18. Normal Regulation of Plasma Glucose in the
Fasted state (release of stored fuel)
Hepatic
Glucagon response
+Glucose released
Muscle/Fat
Glucagon response
+Glucose exits
increased
glucose production
Lower insulin mediated
glucose clearance
+Glucagon
Secretion
- Insulin
Suppression
Normal Fasting
plasma glucose
12
Less Glucose enters
peripheral tissues
More Glucose enters
the blood

19. • 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
– Glucagon stimulated hepatic glucose production
– Fasting substrate availability
• In type 2 diabetes
– Basal insulin secretion is impaired
– Hepatic sensitivity to insulin is decreased
Regulation of Fasting Glucose

20. Normal Regulation of Plasma Glucose in the
Fed State (storage of fuel)
Hepatic
insulin response
- glucose release
Muscle/fat
insulin response
+ glucose uptake
Controlled
glucose production
Controlled
glucose clearance
+ Insulin
Secretion
- Glucagon
Suppression
Normal post prandial
plasma glucose
12
More Glucose enters
peripheral tissues
Less Glucose enters
the blood

21. • A meal contains 6 to 20 times the glucose content
of the blood triggering increased insulin levels and
decreased glucagon levels
• Postprandial hyperglycemia is regulated by
– Clearance of ingested glucose by the liver
– Suppression of hepatic glucose production by
insulin
– Insulin stimulated peripheral clearance of glucose
– Fat storage in adipose tissue
Regulation of Postprandial Glucose

22. Mean Rates of Insulin and Glucagon Delivery From an Artificial
Pancreas at Various Blood Glucose Levels

23. • 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
• Postprandial hyperglycemia results
Impaired Regulation of
Postprandial Glucose

24. Patterns of Glucose, Insulin, and Glucagon
After Oral Glucose in Type 2 Diabetes
–60 0 60 120 180 240 300
60
30
45
400
Type 2 Diabetes
Normal
0
120
240
360
–60 0 60 120 180 240 300
Delayed and reduced
High and not suppressed
Postprandial hyperglycemia
Minutes Minutes
–60 0 60 120 180 240 300
Minutes
300
200
100
Mitrakou A et al. Diabetes. 1990;39:1381-1390
Insulin(pmol/L)
Glucagon(fmol/L)
Glucose(mg/dL)

25. Measures of Hyperglycemia
• Random plasma glucose (RPG)—without regard to
time of last meal
• Fasting plasma glucose (FPG)—before breakfast
• Oral glucose tolerance test (OGTT)—2 hours after a
75-g oral glucose drink
5

26. Measures of Hyperglycemia
• Postprandial plasma glucose (PPG)—2 hours after
a meal
• Hemoglobin A1c (A1C)—reflects mean glucose over
2–3 months
• Fructosamine/glycated serum protein—reflects
mean glucose over 1–2 weeks
5

27. American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10
*Requires confirmation by repeat testing
Symptoms of diabetes plus
random plasma glucose 200 mg/dL*
or
FPG 126 mg/dL*
or
2-h PG during a 75-g OGTT 200 mg/dL*
Making the Diagnosis of Diabetes
20

28. IFG and IGT
Intermediate Between Normal and Diabetes
Impaired Glucose Tolerance (IGT)
• 2-h PG on OGTT
140 but 200 mg/dL
• Predicts increased risk of
diabetes and cardiovascular
disease
Impaired Fasting Glucose (IFG)
• FPG 100 but 126 mg/dL
• Predicts increased risk
of diabetes and micro-
and macrovascular
complications
9

29. Glucose Tolerance Categories
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10
FPG 2-h PPG (OGTT)
126
60
80
100
120
140
160
180
200
Plasma glucose
(mg/dL)
Normal
Diabetes
Mellitus
240
220
Diabetes
Mellitus
Normal
IGT
IFG
8

30. Classification of Diabetes Mellitus
by Etiology
Type 1 -cell destruction—complete lack of insulin
Type 2 -cell dysfunction and insulin resistance
Gestational -cell dysfunction and insulin
resistance during pregnancy
Other specific types • Genetic defects of -cell function
• Exocrine pancreatic diseases
• Endocrinopathies
• Drug- or chemical-induced
• Other rare forms
11

31. Differential Diagnosis
Type 1 and Type 2 Diabetes
Type 1 Diabetes Type 2 Diabetes
Usual clinical course Insulin-dependent Initially non-insulin-
dependent
Usual age of onset <20 years (but ~50% >40 years but
over 20 years) increasingly earlier
Body weight Usually lean Usually obese
Clinical onset Often acute Subtle, slow
Ketosis-prone Yes No
Family history 15% with 1° relative Common
Ethnicity Predominantly white More common in minorities
Frequency of HLA-DR3, Increased Not increased
DR4, DQB1*0201, *0302
Islet autoantibodies Present Absent
(GADA, ICA, IA-2A, IAA)

32. Hyperglycemia
Pathogenesis of Type 1 Diabetes
One Defect
Unrestrained
glucose production
Impaired glucose
clearance
No hepatic
insulin effect
No muscle/fat
insulin effect
Absent
insulin
secretion
Glycosuria 13
More glucose enters
the blood
Less glucose enters
peripheral tissues

33. Putative
trigger
Circulating autoantibodies (ICA, GAD65)
Cellular autoimmunity
Loss of first-phase
insulin response (IVGTT)
Glucose intolerance
(OGTT)
Clinical
onset—
only
10% of
-cells
remain
Time
-Cell
mass 100%
“Pre”-
diabetes
Genetic
predisposition
Insulitis
-Cell injury
Eisenbarth GS. N Engl J Med. 1986;314:1360-1368
Diabetes
Natural History Of “Pre”–Type 1 Diabetes
14

34. Late-Onset Type 1 Diabetes
• About half of patients with type 1 diabetes are diagnosed
after age 18
• Autoimmune process may differ and is slower
• Often mistaken for type 2 diabetes—may make up 10%–30%
of individuals diagnosed with type 2 diabetes
• Can be identified by ICA(Islet Cell Antibodies or GAD
(Glutamic Acid Decarboxylase) antibodies
• Oral agents are usually ineffective—insulin therapy is
eventually required
Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:308-315 15

35. Pathogenesis of Type 2 Diabetes
Two Defects
Excessive
glucose production
Impaired glucose
clearance
Hepatic
insulin
resistance
Muscle/fat
insulin
resistance
Impaired
insulin
secretion
Hyperglycemia
16
More glucose enters
the blood stream
Less glucose goes into
peripheral tissues
Glycosuria

36. Etiology of Type 2 Diabetes
Impaired Insulin Secretion and Insulin Resistance
Genes and environment
Type 2 diabetes
Impaired glucose
tolerance
Impaired insulin
secretion
Insulin resistance+

37. Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789
Natural History of Type 2 Diabetes
Macrovascular complications
Microvascular complications
Insulin resistance
Impaired
glucose tolerance
Undiagnosed
diabetes Known diabetes
Insulin secretion
Postprandial glucose
Fasting glucose
17

38. • Basal hyperglycemia
– Basal insulin levels and hepatic response mainly
determine fasting plasma glucose
• Postprandial hyperglycemia
– Early insulin B- cell release, glucagon suppression, and
hepatic and muscle responses to insulin determine
postprandial glucose levels
Summary of Pathophysiology

39. • Type 1 diabetes
– The main abnormality is insulin deficiency
• Type 2 diabetes
– Both insulin deficiency and insulin resistance
contribute
• Glucotoxicity and lipotoxicity
– Poor metabolic control worsens insulin deficiency and
insulin resistance
Summary of Pathophysiology

40. Summary
Essential Features of Diabetes
• Hyperglycemia, which causes tissue injury and medical
complications
• In type 1 diabetes, insulin secretion is markedly impaired
or absent
• In type 2 diabetes, progressively impaired insulin secretion
and insulin resistance in muscle, fat, and liver
• A1C is a measure of long-term glycemic control
22

41. Gestational Diabetes
• Hyperglycemia during pregnancy—usually resolves
after birth. Type 2 DM usually present at the pre-
natal visit
• Complicates ~7%(range of 1%- 14%) of all
pregnancies in the United States resulting in 200,
000 cases annually
• High risk of perinatal morbidity and mortality
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S88-S90 18

42. Gestational Diabetes
• High risk of later type 2 diabetes in both mother
and baby (should be screened 6-12 weeks
postpartum and followed)
• Diagnosed by specific glucose tolerance test
methods
• Requires intensive dietary and glycemic
management
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S88-S90 18

43. Fetal
hyperinsulinemia
The Impact of Maternal Hyperglycemia
During Pregnancy
Modified Pedersen Hypothesis
Fetus
Fetal pancreas stimulated
IgG=immunoglobulin G
Mother
Placenta
IgG-antibody-bound insulin
Insulin
Maternal hyperglycemia
Insulin resistance syndrome

44. Approximate Prevalence of Diabetes
in Pregnancy in the United States
GDM=gestational diabetes mellitus
Nondiabetes
92%
More than 200,000 type 2 diabetes mellitus + 200,000 GDM + 6000 type 1 diabetes
mellitus = 406,000 pregnancies complicated by hyperglycemia annually
Diabetes 8%
4.022 Million Births in 2002
50% GDM
Diabetes 8%
2% T1DM
24% Diagnosed T2DM
24% Undiagnosed T2DM

45. GDM Screening and Diagnosis
American Diabetes Association Guidelines
High risk: Screen at first prenatal visit
Average risk: Screen at 24 to 28 weeks’ gestation
Low risk: No screening
FPG 1-hour 2-hour 3-hour
plasma glucose plasma glucose plasma glucose
Screening:
1-h GCT (50 g) NA >140 mg/dL NA NA
Diagnosis:
3-h OGTT (75 g)* 95 mg/dL 180 mg/dL 155 mg/dL NA
(100 g)* 95 mg/dL 180 mg/dL 155 mg/dL 140 mg/dL
*Two or more measurements must be met for diagnosis
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S88-S90
FPG=fasting plasma glucose
GCT=glucose challenge test
OGTT=oral glucose challenge test
NA=not applicable

46. GDM Screening and Diagnosis
Universal Screening Guidelines
Average and high risk: Screen at intake
Low risk: Screen at 24 to 28 weeks’ gestation
Screen with
1-h 50-g GCT
180 mg/dL
STOP
Patient has GDM
140–180 mg/dL
Administer FPG and
3-h 100-g OGTT
on separate day
140 mg/dL
STOP
Patient does not
have GDM
If FPG 95 mg/dL
STOP
Patient has GDM
Otherwise, administer
3-h 100-g OGTT
(2 or more abnormal
values,
patient has GDM)
1 h 180 mg/dL
2 h 155 mg/dL
3 h 140 mg/dL
If patient has GDM
risk factors,
rescreen at 24–28
weeks’ gestation
Rescreen later in
gestation
FPG=fasting plasma glucose
Jovanovic-Peterson L et al. Am J Perinatol. 1997;14:221-228

47. Fasting whole blood or plasma glucose
>90 mg/dL
and/or
1-hour postprandial whole blood or plasma glucose
>120 mg/dL
Two or more abnormal measurements over 1 to 2 weeks
Insulin Delivery Throughout Pregnancy
Indications for Insulin Therapy in GDM
Jovanovic L, ed in chief. Medical Management of Pregnancy Complicated by Diabetes.
3rd ed. Alexandria, Va: American Diabetes Association; 2000:111-132

48. Acute Complications of Diabetes Mellitus
• Hyperglycemia-
polyuria,nocturia,dehydration,polydypsia,polyphagia
weight loss, increased plasma osmolality
• Diabetic Ketoacidosis-
severe insulin deficiency, lipolysis and ketogenesis,
fluid and electrolyte shifts, volume contraction,
counter regulatory hormones, coma, metabolic
acidosis, hyperlipidemia, nausea, vomiting,
abdominal pain, high wbc

49. Acute Complications of Diabetes Mellitus
• Hyperosmolar Non-Ketotic Coma
absence of ketosis, severe water deficit, elderly and
renal insufficiency, later presentation, profound
dehydration, high insulin sensitivity
• Hypoglycemia
often with fasting or exercise, a complication of
insulin or oral agent treatment, acute response is
from glucagon and cathecolamines

50. Chronic Complications of Diabetes Mellitus
• Retinopathy, nephropathy, neuropathy
• Cardiovascular disorders
• Infections, cataracts, connective tissue disorders
3

51. Hyperglycemia Damages Tissues
• Effects of hyperglycemia
– Glycation of proteins (eg, hemoglobin, collagen)
– Accumulation of sorbitol and fructose (eg, in nerves, lens)
– Activation of protein kinase C (eg, on vascular cells)
• Tissue changes
– Altered protein function and turnover, cytokine activation
– Osmotic and oxidative stress
– Reduced motor and sensory nerve conduction velocity
– Increased glomerular filtration rate and renal plasma flow
2

52. Hyperglycemia
The Defining Feature of Diabetes
Hyperglycemia
Excessive
glucose production
Impaired
glucose clearance
Tissue injury
1

53. Hyperglycemia
Two Mechanisms of Tissue Injury
from Hyperglycemia
Brownlee M. Metabolism. 2000;49(suppl 1):9-13; Greene DA et al. N Engl J Med.
1987;316:599-606; Sheetz MJ, King GL. JAMA. 2002;288:2579-2588
Glycation
pathway
Sorbitol
pathway
Sorbitol and fructoseGlycated proteins
(eg, A1C)
Oxidative
effects
Osmotic
effects
Advanced glycation
end products (AGEs)
Altered function
or turnover
Receptor-mediated
cytokine effects
4

54. The Sorbitol Pathway -
Hyperglycemia Increases Intracellular
Sorbitol

55. Glucose FFA
FFA
Increased
glucosamine
Other
pathways
Other
pathways
Glucose
Impaired insulin
secretion from -cell
Insulin resistance
in muscle and fat
Mechanism of Glucotoxicity and Lipotoxicity
The Glucosamine Hypothesis
Hawkins M et al. J Clin Invest. 1997;99:2173-2182; Rossetti L. Endocrinology.
2000;141:1922-1925
FFA=free fatty acid

56. Therapeutic Options for Type 2 Diabetes
Secretagogues
Sensitizers
Prandial Regulators
Incretins
Renal Glucose Uptake inhibitors

57. Oral Antihyperglycemic Agents
for Type 2 Diabetes
Class Agents
Secretagogue Sulfonylureas
Repaglinide, nateglinide
Biguanide Metformin
α-Glucosidase inhibitor Acarbose, miglitol
Glitazone (TZD) Pioglitazone, rosiglitazone

58. Oral Antihyperglycemic Agents
for Type 2 Diabetes
Class Agents
Renal Glucose Threshold Canagliflozin, Dapagliflozin
Inhibitors Empagliflozin
Selective sodium-glucose
Transpt-2 Inhibitor
(SGLT-2)

59. Oral and Injectable Antihyperglycemic Agents
for Type 2 Diabetes
Class
Incretins Agents
Glucagonlike peptide-1 Exenatide, Liraglutide,
(GPL-) agonists Albiglutide, Dulaglutide
Dipeptidyl peptidase IV Sitagliptin, Saxagliptin
(DPP-4) Inhibitors Linagliptin, Alogliptin

60. Insulin Secretagogues
Sulfonylureas, Repaglinide, and Nateglinide
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
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

61. Selected Insulin Secretagogues
Dosing Information
Recommended Usual
Generic Name Dose Strengths Dose Range Maximal Effect
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

62. Biguanides
Metformin
Riddle MC. Am Fam Physician. 1999;60:2613-2620;
Cusi K et al. Diabetes Rev. 1998;6:89-131
Primary mechanism Decreases hepatic glucose
of action production
Efficacy depends upon Presence of insulin
Power Decreases A1C 1%–2%
Dosing 2 or 3 times daily (metformin)
1 or 2 times daily (metformin XR)
Side effects Diarrhea, nausea
Main risk Lactic acidosis

63. Metformin, a-Glucosidase Inhibitors,
Glitazones
Dosing Information
Recommended Usual
Generic Name Dose Strengths Dose Range Maximal Effect
Metformin 500, 850, or 500 mg qd to 1000 mg bid
1000 mg 850 mg tid
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

64. 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

65. Glitazones (TZDs)
Pioglitazone and Rosiglitazone
Mechanism of action Enhance tissue response to insulin
Efficacy depends upon 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

66. 65
Incretins
Sitigliptin (Januvia)
Primary mechanism Inhibits dipeptidyl- peptidase IV
of action (DPPT- IV) degradation of GPL-1
Efficacy depends upon Presence of GPL-1 and insulin
Power Decreases A1C 1%–2%
Dosing 100mg/day with or without meals
25-50mg/day for renal disease
Side effects Diarrhea, nausea

67. 66
Incretins
Saxagliptin (Onglyza)
Primary mechanism Inhibits dipeptidyl- peptidase IV
of action (DPPT- IV) degradation of GPL-1
Efficacy depends upon Presence of GPL-1 and insulin
Power Decreases A1C 1%–2%
Dosing 2.5-5/day with or without meals
2.5mg/day for renal disease
Side effects Diarrhea, nausea

68. 67
Incretins
Liraglutide (Victoza)
Primary mechanism Incretin(GPL-1) analogue
of action prolonging the half-life of GPL-1
Efficacy depends upon Presence of GPL-1 and insulin
Power Decreases A1C .5%–1%
Dosing 0.6mg SQ daily for one week
then 1.2mg SQ daily
Side effects Diarrhea, nausea; +weight loss

69. 68
Amylinomimetic
Pramlintide (Symlin)
Primary mechanism analogue of human amylin (co-
of action secreted with insulin from B-cell)
Efficacy depends upon Presence of insulin, intact B-cells
Power Decreases A1C .5%–1%
Dosing Administered before meals SQ at
the time insulin is administered
Side effects Headache, nausea; hypoglcemia

70. Antihyperglycemic Agents
Major Sites of Action
Carbohydrate absorption
Glucose production
Insulin secretion
Secretagogues
Glucose uptake
Injected
insulin
Glitazonesa-Glucosidase inhibitors
–
+
+
+
Pancreas
Metformin
Muscle/Fat
–
–
–
+
GI tract
Liver
Plasma glucose

71. Assessing Patient Outcomes
Glycemic Control
• SMBG
– Reflects basal and postprandial glucose and
determines whether target levels are achieved
– Identifies patterns, variability, and guides changes of
treatment
• A1C
– Reflects mean glucose and determines whether target
control is achieved

72. Assessing Outcomes
Self-Monitoring of Blood Glucose
100
200
300
Plasma glucose
mg/dL
0800 1200 1800 0800
Time
Breakfast Lunch Supper Bedtime
Fasting
Preprandial Preprandial
Normal
Uncontrolled diabetes
SMBG
Postprandial

73. 300
200
100
0
Plasma
glucose
(mg/dL) Postprandial hyperglycemia
Fasting
hyperglycemia
Riddle MC. Diabetes Care. 1990;13:676-686
Time of day
0600 1200 1800 2400 0600
The Therapeutic Problem
Controlling Both Fasting
and Postprandial Hyperglycemia
Uncontrolled diabetes
with A1C ~8%
Normal glycemic exposure
A1C ~5%

74. 300
200
100
0
Plasma glucose
(mg/dL)
Postprandial
hyperglycemia
Normal
Fasting
hyperglycemia
Riddle MC. Diabetes Care. 1990;13:676-686
Time of day
0600 1200 1800 2400 0600
A1C Reflects Both Fasting and
Postprandial Hyperglycemia
6

75. Primary Objectives of Effective Management
A1C
%
SBP
mm Hg
LDL
mg/dL
45 50 55 60 65 70 75 80 85 90
9
Diagnosis
8
7
130
100
145
140
Patient Age
Reduction
of both
micro- and
macrovascular
event
rates
…by 75%!

76. Summary of
Oral Antihyperglycemic Agents
• Six 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
a-glucosidase inhibitors and nateglinide
• A1C reductions are similar using sulfonylureas, metformin,
and glitazones
• Secondary failure to monotherapy routinely occurs

78. Therapeutic Options
Insulins

79. 78
Insulin Preparations
Class Agents
Human insulins Regular(Humulin R, Novolin R),
NPH(Humulin N, Novolin N), lente,
Ultralente
Insulin analogues Aspart, glulisine, lispro, glargine,
detemir
Premixed insulins Humulin 70%/30%, 50/50
Humalog mix 75/25,Novolog mix70/30

80. 79
Human Insulin
A-chain
B-chain
Zn++
Zn++
Self-aggregation
in solution
Monomers
Dimers
Hexamers
21 amino acids
30 amino acids

81. 80
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 and
Large crystals in acetate-Zn2+ buffer long acting

82. 81
Profiles of Human Insulins
0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Plasma
insulin
levels
Regular 6–8 hours
NPH 12–20 hours
Ultralente 18–24 hours
Hours

83. 82
Insulin Analogues
Human Insulin
Dimers and hexamers
in solution
A-chain
B-chain
Lys Pro
Gly
Arg Arg
Asp
Lispro(Humalog)
Limited self-aggregation
Monomers in solution
Aspart(NovoLog)
Limited self-aggregation
Monomers in solution
Glargine(Lantus)
Soluble at low pH
Precipitates at
neutral (subcutaneous) pH
Glu
Glulisine(Apidra)
Limited self-aggregation
Monomers in solution
Lys

84. 83
Human Insulins and Analogues
Typical Times of Action
Insulin
Preparations
Onset of Action Peak Duration of
Action
Aspart,
glulisine, lispro
~15 minutes 1–2 hours 4–6 hours
Human regular 30–60 minutes 2–4 hours 6–8 hours
Human NPH,
lente
2–4 hours 4–10 hours 12–20 hours
Human
ultralente
4–6 hours 8–16 hours 18–24 hours
Glargine 2–4 hours Flat ~24 hours

85. 84
500
400
300
200
100
0
Insulin Aspart(NovoLog)
A Rapid-Acting Insulin Analogue
Plasma Insulin
Mudaliar SR et al. Diabetes Care. 1999;22:1501-1506
Insulin Action
pmol/L
700
600
500
400
300
200
100
0
Minutes
0 100 200 300 400 500 600 0 100 200 300 400 500 600
Glusose
infusion
rate
(mg/min)
Insulin aspart
Regular insulin
20 Healthy Subjects, 10-h Euglycemic Clamp

86. 85
Insulin Lispro(Humalog)
A Rapid-Acting Insulin Analogue
Heinemann L et al. Diabet Med. 1996;13:625-629
Insulin lispro
Regular insulin
-60 -30 0 30 60 90 120 150 180 210 240
Minutes
mg/dLpmol/L
400
-60 -30 0 30 60 90 120 150 180 210 240
Meal
and
insulin
Meal
and
insulin
Plasma Insulin Plasma Glucose
10 Patients With Type 1 Diabetes Following a Meal
300
200
100
0
200
150
0
100

87. 86
Action Profiles of Insulin Analogues
0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Plasma
insulin
levels
Regular(Humulin R, Novolin R) 6–8 hours
NPH(Humulin N, Novolin N) 12–20 hours
Ultralente 18–24 hours
Hours
Glargine(Lantus) 24 hours
Aspart(NovoLog), glulisine(Apidra), lispro(Humalog) 4–6 hours

88. 87Polonsky KS et al. N Engl J Med. 1988;318:1231-1239
0600 0600
Time of day
20
40
60
80
100
B L D
Normal Daily Plasma Insulin Profile
B=breakfast; L=lunch; D=dinner
0800 18001200 2400
U/mL
Plasma
Insulin

89. 88
The Basal-Bolus Insulin Concept
• Basal insulin
– Controls glucose production between meals and overnight
– Nearly constant levels
– 50% of daily needs
• Bolus insulin (mealtime or prandial)
– Limits hyperglycemia after meals
– Immediate rise and sharp peak at 1 hour postmeal
– 10% to 20% of total daily insulin requirement at each meal
• For ideal insulin replacement therapy, each component should
come from a different insulin with a specific profile

90. 89
0600 0800 18001200 2400 0600
Time of day
20
40
60
80
100
B L D
Basal-Bolus Insulin Treatment
With Insulin Analogues
B=breakfast; L=lunch; D=dinner
Glargine(Lantus)
Ditmir (Levimir)
Lispro(Humalog), glulisine(Apidra), or aspart(NovoLog)
Normal pattern
U/mL

91. 90
Barriers to Using Insulin
• Patient resistance
– Perceived significance of needing insulin
– Fear of injections
– Complexity of regimens
– Pain, lipohypertrophy
• Physician resistance
– Perceived cardiovascular risks
– Lack of time and resources to supervise treatment
• Medical limitations of insulin treatment
– Hypoglycemia
– Weight gain

92. 91
Insulin Injection Devices
Insulin pens
• Faster and easier
than syringes
– Improve patient attitude
and adherence
– Have accurate dosing
mechanisms, but
inadequate mixing may
be a problem

93. 92
Insulin Pumps
Continuous subcutaneous insulin infusion
(CSII)
– External, programmable pump
connected to an indwelling
subcutaneous catheter to deliver
rapid-acting insulin
Intraperitoneal insulin infusion
– Implanted, programmable
pump with intraperitoneal catheter.
Not available in the United States

94. 93
Summary
Insulin Therapy
• Replaces complete lack of insulin in type 1 diabetes
• Supplements progressive deficiency in type 2 diabetes
• Basal insulin added to oral agents can be used to start
• Full replacement requires a basal-bolus regimen
• Hypoglycemia and weight gain are the main medical risks
• New insulin analogues and injection devices facilitate use

95. Intervention Advantages Challenges
Lifestyle modification to decrease weight
and increase activity
Broad benefits Insufficient for most within first year
Metformin Weight neutral GI side effects, contraindicated with renal
insufficiency
Insulin No dose limit, rapidly effective,
improved lipid profile
1-4 injections daily, monitoring, weight gain,
hypoglycemia, analogs are expensive
Sulfonylurea Rapidly effective Weight gain, hypoglycemia (especially with
blibenclamide or chlorpropamide)
TZDs Improved lipid profile
(pioglitazone), potential decrease
in MI (pioglitazone)
Fluid retention, CHF, weight gain, bone fractures,
expensive, question of increased MI risk
(rosiglitazone)
GLP-1 receptor agonists (exenatide,
liraglutide)
Weight loss and low risk of
hypoglycemia
Administration (injections), frequent GI side
effects, long-term safety not established,
expensive
Summary of available Glucose-lowering interventions

96. Intervention Advantages Challenges
Alpha-glucosidase inhibitor Weight neutral Frequent GI side effects, 3-times-daily dosing,
expensive
Glinide Rapidly effective Weight gain, 3-times-daily dosing, hypoglycemia,
expensive
Pramlintide Weight loss 3 injections daily, frequent GI side effects, long-
term safety not established, expensive
DPP-4 inhibitors Weight neutral and low risk of
hypoblycemia
Long-term safety not established, expensive
Bile acid sequestrant Lowers LDL cholesterol Can increase triglycerides; can cause
constipation
Quick-release bromocriptine mesylate Weight neutral; low risk of
hypoglycemia
Initial nausea
Summary of available Glucose-lowering interventions (cont)
CHF indicates congestive heart failure; DPP-4, dipeptidly peptidase-4; GI gastrointestinal; GLP-1, glucagon-like peptide-1; LDL, low-density lipoprotein; MI, myocardial infarction;
TZDs, thiazolidinediones.

97. 96
Sequential and Overlapping Therapies
for Type 2 Diabetes
Pre-diabetes Type 2 Diabetes
0
Onset Diagnosis
Years from diagnosis
Years of age
65
Insulin
Metformin
Secretagogues
a-Glucosidase Inhibitors
Glitazones
40 45 50 55 60
5-10 -5 10 15
Lifestyle

98. Tier 1: Well-validated core
therapies
At diagnosis:
Lifestyle + metformin
Lifestyle + metformin
+ basal insulin
Lifestyle + metformin
+ sulfonlyuria a
Lifestyle + metformin
+ intensive insulin
Step 1 Step 2 Step 3
Tier 2: Less well-validated
therapies
Lifestyle + metormin
+ pioglitazone
Lifestyle + metformin
+ GLP-1 agonist b
Lifestyle + metformin
+ pioglitazone + sulfonylurea a
Lifestyle + metformin
+ basal insulin
Reinforce lifestyle interventions at every visit; check A1C every 3 months until A1C is <7% and then at least
every 6 months. The interventions should be changed if A1C is ≥7%.
ADA indicates American Diabetes Association; EASD, European Association for the Study of Diabetes; GLP-1, glucagon-like peptide-1.
a Sulfonylureas other than glyburide or chlorpropamide.
b Insufficient clinical use to be confident regarding safety.
Adapted from Nathan DM, et al. Diabetes Care. 2009;32:193-203.

99. Start with bedtime intermediate-acting insulin or
bedtime or morning long-acting insulin (can initiate
with 10 units or 0.2 units per kg)
Check fasting glucose (fingerstick) usually daily and increase dose,
typically by 2 units every 3 days until fasting levels are consistently in
target range (3.9-7.2 mmol/l [70-130 mg/dl]).Can increase dose in larger
increments, e.g., by 4 units every 3 days, if fasting glucose is >10 mmol/l
(180 mg/dl)
If hypoglycemia occurs,
or fasting glucose level
<3.9 mmol/l (70 mg/dl),
reduce bedtime dose by
4 units or 10%
whichever is greater
A1C ≥7% after 2-3 months
No Yes
Continue regimen,
Check A1C every
3 months
If fasting bg is in target range (3.9-7.2 mmol/l [70-130
mg/dl]), check bg before lunch, dinner and bed. Depending
on bg results, add second injection as below. Can usually
begin with ~4 units and adjust by 2 units every 3 days until
bg is in range
Pre-lunch bg out
of range, add
rapid-acting
insulin at
breakfast
Pre-dinner bg out of
range. Add NPH
insulin at breakfast or
rapid-acting at lunch
Pre-bed bg out of
range. Add rapid-
acting insulin at
dinner.
A1C ≥7% after 3 months
Recheck pre-meal bg levels and if out of range,
may need to add another injection. If A1C
continues to be out of range, check 2 h
postprandial levels and adjust preprandial
rapid-acting insulin
No
Yes