Shafei dm

Wednesday, January 20, 2016 3
The first known mention of
diabetes symptoms was in 1552 B.C.,
when Hesy-Ra, an Egyptian
physician, documented frequent
urination as a symptom of a
mysterious disease that also caused
emaciation
History of the DiseaseHistory of the Disease

Prosthetic, wood & leather “great toe”
found on foot of Egyptian mummy

5
1500 BC ,Indian hindu discovered that
ants sinks in the urine of kings and rich
people and found their urine is sweety .
150 AD, the Greek physician Arateus
described what we now call diabetes as
"the melting down of flesh and limbs into
urine." diabetes” means “
to pass through like siphon. And
mellitus means sweeten like honey .
“sweet flow” in ancient Greek as
opposed to diabetes insipidus (which
means “tasteless” in Latin)

AvicennaAvicenna, a famous Arab physician, described the, a famous Arab physician, described the
complications of the diseasecomplications of the disease and how itand how it
progressedprogressed
French physician BouchardatFrench physician Bouchardat recognized therecognized the
importance of calorie intakeimportance of calorie intake in the 1870sin the 1870s
http://www.pre-renaissance.com/images/avicenna2.jpghttp://www.pre-renaissance.com/images/avicenna2.jpg

The American Diabetes Association
(ADA) reports that in 1910, medical
professionals took the first steps
toward discovering a cause and
treatment mode for diabetes. Edward
Albert Sharpey-Shafer announced that
the pancreas of a diabetes patient was
unable to produce what he termed
“insulin,” a chemical the body uses to
break down sugar. Thus, excess sugar
ended up in the urine. Physicians
promoted a fasting diet combined with
regular exercise to combat the
disorder. But victems inevitably die.
Edward Albert Sharpey-Shafer

Paul Langerhans identified the importance of the pancreas in the
early 19th
century and discovered the islets of Langerhans, a group
of cells that would later be known to produce insulin
(Latin ward of islets)

9
Paul Langerhans
Berlin in 1869
Oscar Minkowski
1889, Polish-German
Nicolae Paulescu
1916, a Romanian professor
Frederick BantingMaclodChales Best

10
. In 1921, scientists experimenting
with dogs had a breakthrough in
reversing the effects of diabetes.
Two Canadian researchers
Frederick Grant Banting and Charles Herbert Best
successfully extracted insulin from
healthy dogs. They then injected it
into diabetic dogs to improve their
condition.

 In Jan, 1922, Banting and Best injected a 14-
year-old "charity” patient who weighed 64 lb
with 7.5 ml of a "thick brown muck“ in each
buttock
 Abscesses developed and he became more
acutely ill
 However, his blood glucose had dropped
enough to continue refining what was called
"iletin” insulin
 6 weeks later, a refined extract caused his
blood glucose to fall from 520 to 120 mg/dL in
24 hours
 Leonard lived a relatively healthy life for 13
years before dying of pneumonia (no Rx then)
at 27

Herbert Boyer 1977
Synthesis of humaline
Dorothy Crowfoot 1969 ,3ry
structure
1977 Rosalyn
radioimmunoassay for insulin
Frederick Sanger
1958 british molecular
biologist, 1ry structure

• 1922 Banting and Best use bovine insulin extract on human
• 1923 Lilly produces commercial quantities of bovine insulin
• 1936 Hagedorn discovers that adding protamine to insulin prolongs the effect of
insulin
• 1946 Nordisk formulates Isophane® porcine insulin aka Neutral Protamine
Hagedorn or NPH insulin
• 1950 Nordisk markets NPH insulin
• 1953 Novo formulates Lente® porcine and bovine insulins by adding zinc for
longer lasting insulin
• 1978 Genentech produces human insulin in Escheria coli bacteria using
recombinant DNA
• 1981 Novo Nordisk chemically and enzymatically converts bovine to human
insulin
• 1982 Genentech human insulin approved
• 1983 Lilly produces recombinant human insulin, Humulin®
• 1988 Novo Nordisk produces recombinant human insulin
• 1996 Lilly Humalog® "lyspro" insulin analogue approved
• 2003 Aventis Lantus® "glargine" insulin analogue approved in USA
• 2006 Novo Nordisk's "Detemir" approved in USA
• 2007, the currently available type (Exubera)

HISTORY OF INSULIN
PUMPS
o 1960’s ,First introduced by a Physician called
Dr. Arnold Kadish.
o 1974, First non-portable computer controlled
insulin pump.
o 1978, First commercially available portable
insulin pump called the Autosyringe “Big Blue Brick”.
o 1983, Medtronic releases the first small
programmable insulin
pump into the market.

INSULIN PUMPS
TODAY
► ACCU-CHEK SPIRIT – ROCHE
► AMIGO – NIPRO CORPORATION
► DANA DIABECARE 11S – SOAIL DEVELOPMENT
► MINIMED PARADIGM REVEL – MEDTRONIC
► OMNIPOD – INSULET CORPORATION
► ONE TOUCH PING – ANIMAS CORPORATION

Insulin/amylin
glucagon
somatostatin

Effect of insulin on the
glucose permeability of cells
Insulin binds to
receptors on cell
surface membranes
intracellular
chemical
signal
signal triggers the
fusion of carrier-
containing vesicles
with the surface
membrane
The additional
carriers increase
glucose
permeability
glucose carrier for
facilitated diffusion
plasma
membrane

Glucose to glycogenGlycogen to glucose
non-carbohydrates to glucose
detected by the
alpha cells
detected by the
beta cells
glucagon secretion insulin secretion
release of fatty
acids from
adipose tissue
uptake of
glucose for
fatty acid
synthesis
increased
permeability of
body cells to glucose
Dual Hormonal
Control achieves
Glucose Homeostasis

Insulin and glucose

Zinc transporter
Pancreatic islet β cells
(tyrosine phosphatase I-A2)

Start with the Natural History of Diabetes
Years
Glucose(mmol/L)RelativeFunction
-10 -5 0 5 10 15 20 25 30
2.8
5.6
8.3
11.1
14
17
19
Insulin resistance
Insulin level
Fasting glucose
Post-meal glucose
Onset
Diabetes
Onset
Diabetes
Pre-diabetes
metabolic syndrome
0
50
100
150
200
250
-15
Incretin action
β cell function

The Ominous Octet
Islet β-cell
ImpairedImpaired
Insulin SecretionInsulin Secretion
Decreased GlucoseDecreased Glucose
UptakeUptake
Islet α-cell
IncreasedIncreased
Glucagon SecretionGlucagon Secretion
IncreasedIncreased
LipolysisLipolysis
Increased GlucoseIncreased Glucose
ReabsorptionReabsorption
IncreasedIncreased
HGPHGP
DecreasedDecreased
Incretin EffectIncretin Effect
DeFronzo Diabetes 2008

Insulin Resistance and β-cell dysfunction produce
Hyperglycemia in Type 2 diabetes
Pancreatic β-cell Insulin resistance
Hyperglycemia
β-cell dysfunction
Adipose Tissue
Decreased glucose transport
(GLUT 4)
Increased
lipolysis
+ -
Low plasma
insulin
Increased glucose output
Adipocytokines
Elevated
plasma FFA

Insulin Deficiency: Impaired β-Cell Function
Normal versus Type 2 Diabetes
0 2 4 6 8 10 12 14 16
Time (hours)
SecretedInsulin
(ng/ml/islet)
18
0.5
1.0
1.5
2.0
2.5
11.1 mmol/L (200 mg/dL) Glucose
Normal
Diabetes
Grodsky GM , Diabetes 1989; 38:673

Muller WA, et al. N Engl J Med. 1970;283:109-115.
80
100
120
140
160
–60 0 60 120 180 240
Time (min)
Glucagon(pg/mL)
0
50
100
150
–60 0 60 120 180 240
Insulin(μU/mL)
NGT NGT
Islet dysfunction:
Inappropriate Insulin and Glucagon
Responses to Glucose in Patients With T2DM
Insulin Glucagon

Muller WA, et al. N Engl J Med. 1970;283:109-115.
80
100
120
140
160
–60 0 60 120 180 240
Time (min)
Glucagon(pg/mL)
0
50
100
150
–60 0 60 120 180 240
Insulin(μU/mL)
NGT
T2DM
NGT
T2DM
Insulin Glucagon
Islet dysfunction:
Inappropriate Insulin and Glucagon
Responses to Glucose in Patients With T2DM

β-cellFunction
(%ofnormalbyHOMA)
Adapted from Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25.
Years
0
20
40
60
80
100
−10 −9 −8 −7 −6 −5 −4 −3 −2 −1 0 1 2 3 4 5 6
Time of diagnosis
?
HOMA = homeostasis model assessment
Decline of β-Cell Function in the UKPDS Illustrates
Progressive Nature of Diabetes

Multiple factors may drive progressive
β-cell dysfunction
β-cell
Hyperglycemia
“glucotoxicity”
Amyloid (IAPP) deposition
Elevated FFA
“lipotoxicity”
Other factors:
Genetic
Age
AGEs
Insulin
Resistance
ER Stress
ER StressER Stress
o Oxidative stress expressed in B-
cell mitochondrial dysfunction
o Incretin dysfunction
decreased glucagon-like peptide-1
(GLP-1) levels with intact
response
normal or elevated glucose-dependent
insulinotropic peptide (GIP) levels
with decreased response

• Type 1 diabetes
– β-cell destruction
• Type 2 diabetes
– Progressive insulin secretory defect
• Other specific types of diabetes
– Genetic defects in β-cell function,
insulin action
– Diseases of the exocrine pancreas
– Drug- or chemical-induced
• Gestational diabetes mellitus (GDM)
ADA. 2. Classification and Diagnosis. Diabetes Care 2015;38(suppl 1):S8

• A complete medical evaluation should be performed to
– Classify the diabetes
• Detect presence of diabetes complications
• Review previous treatment, risk factor control in patients with established diabetes
• Assist in formulating a management plan
• Provide a basis for continuing care
• Perform laboratory tests necessary to evaluate each patient’s
medical condition
Screening Recommendation
• Consider screening those with type 1 diabetes for other
autoimmune diseases (thyroid, vitamin B12 deficiency, celiac) as
appropriate B
Diabetes Care: Initial EvaluationDiabetes Care: Initial Evaluation
ADA. 3. Initial Evaluation and Diabetes Management Planning. Diabetes Care 2015;38(suppl 1):S17

Medical history (1)
• Age and characteristics of onset of diabetes (e.g., DKA, asymptomatic laboratory finding
• Eating patterns, physical activity habits, nutritional status, and weight history; growth and
development in children and adolescents
• Diabetes education history
• Review of previous treatment regimens and response to therapy (A1C records)
Components of the ComprehensiveComponents of the Comprehensive
Diabetes EvaluationDiabetes Evaluation
Medical history (2)
• Current treatment of diabetes, including medications, adherence and barriers thereto, meal plan,
physical activity patterns, readiness for behavior change
• Results of glucose monitoring, patient’s use of data
• DKA frequency, severity, cause
• Hypoglycemic episodes
– Hypoglycemic awareness
– Any severe hypoglycemia: frequency, cause

Diabetes EvaluationDiabetes Evaluation
Physical examination (1)
• Height, weight, BMI
• Blood pressure determination, including orthostatic measurements when
indicated
• Fundoscopic examination
• Thyroid palpation
• Skin examination (for acanthosis nigricans and insulin injection sites)

Diabetes Evaluation (6)Diabetes Evaluation (6)
Laboratory evaluation
• A1C, if results not available within past 3 months
• If not performed/available within past year
– Fasting lipid profile, including total, LDL, and HDL cholesterol and triglycerides
– Liver function tests
– Test for urine albumin excretion with spot urine albumin-to-creatinine ratio
– Serum creatinine and calculated GFR
– TSH in type 1 diabetes, dyslipidemia, or women over age 50 years

Diagnostic Criteria for Prediabetes
and Diabetes in Nonpregnant Adults
63
Normal High Risk for Diabetes Diabetes
FPG <100 mg/dL
IFG
FPG ≥100-125 mg/dL
FPG ≥126 mg/dL
2-h PG <140 mg/dL
IGT
2-h PG ≥140-199 mg/dL
2-h PG ≥200 mg/dL
Random PG ≥200 mg/dL +
symptoms*
A1C <5.5%
5.5 to 6.4%
For screening of prediabetes†
≥6.5%
Secondary‡
*Polydipsia (frequent thirst), polyuria (frequent urination), polyphagia (extreme hunger), blurred
vision, weakness, unexplained weight loss.
†
A1C should be used only for screening prediabetes. The diagnosis of prediabetes, which may
manifest as either IFG or IGT, should be confirmed with glucose testing.
‡
Glucose criteria are preferred for the diagnosis of DM. In all cases, the diagnosis should be
confirmed on a separate day by repeating the glucose or A1C testing. When A1C is used for
diagnosis, follow-up glucose testing should be done when possible to help manage DM.
FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; PG, plasma glucose.
Q1. How is diabetes screened and diagnosed?

Diagnostic Criteria for
Gestational Diabetes
Test Screen at 24-28 weeks gestation
FPG, mg/dL >92
1-h PG*, mg/dL ≥180
2-h PG*, mg/dL ≥153
*Measured with an OGTT performed 2 hours after 75-g oral glucose load.
FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; PG, plasma glucose.
64

Diagnosing Type 1 Diabetes
(T1D)
• Usually characterized by insulin deficiency and
dependency
– Document levels of insulin and C-peptide
• Test for autoantibodies*
– Insulin
– Glutamic acid decarboxylase
– Pancreatic islet β cells (tyrosine phosphatase IA-2)
– Zinc transporter (ZnT8)
• May occur in overweight or obese as well as
lean individuals
*Evidence of autoimmunity may be absent in idiopathic T1D. 67

Criteria for Screening for T2D and
Prediabetes in Asymptomatic Adults
68
*At-risk BMI may be lower in some ethnic groups; consider using waist circumference.
†
Obstructive sleep apnea, chronic sleep deprivation, and night shift occupations.
BMI = body mass index; BP = blood pressure; CVD=cardiovascular disease; HDL-C = high density lipoprotein cholesterol; IFG = impaired fasting
glucose; IGT = impaired glucose tolerance; NAFLD = nonalcoholic fatty liver disease; PCOS = polycystic ovary syndrome; T2D, type 2 diabetes.

Outpatient Glucose Targets for
Nonpregnant Adults
Parameter Treatment Goal
A1C, %
Individualize on the basis of age, comorbidities,
duration of disease, and hypoglycemia risk:
•In general, ≤6.5 for most*
•Closer to normal for healthy
•Less stringent for “less healthy”
FPG, mg/dL <110
2-Hour PPG, mg/dL <140
71
Q3. What are glycemic treatment goals of DM?
FPG = fasting plasma glucose; PPG = postprandial glucose.
*Provided target can be safely achieved.

Targets for glycemic (blood sugar) control in most non-pregnant adults
ADA AACE
A1c (%) <7* ≤6.5
Fasting (preprandial) plasma
glucose 70-130 mg/dL <110 mg/dL
Postprandial (after meal)
plasma glucose <180 mg/dL <140 mg/dL
• American Diabetes Association. Diabetes Care. 2012;35(suppl 1)
• https://www.aace.com/sites/default/files/DMGuidelinesCCP.pdf 2011
*<6 for certain individuals
Goals of Glucose Management

Outpatient Glucose Targets for
Pregnant Women
Condition Treatment Goal
Gestational diabetes mellitus (GDM)
Preprandial glucose, mg/dL ≤95*
1-Hour PPG, mg/dL ≤140*
2-Hour PPG, mg/dL ≤120*
Preexisting T1D or T2D
Premeal, bedtime, and overnight glucose, mg/dL 60-99*
Peak PPG, mg/dL 100-129*
A1C ≤6.0%*
73FPG = fasting plasma glucose; PPG = postprandial glucose.
Q17. How should diabetes in pregnancy be managed?

Medical and Surgical Interventions
Shown to Delay or Prevent T2D
78
T2D, type 2 diabetes.
1. DPP Research Group. N Engl J Med. 2002;346:393-403. 2. STOP-NIDDM Trial Research Group. Lancet. 2002;359:2072-2077.
3. Defronzo RA, et al. N Engl J Med. 2011;364:1104-15. 4. DREAM Trial Investigators. Lancet. 2006;368:1096-1105.
5. Torgerson JS, et al. Diabetes Care. 2004;27:155-161. 6. Garvey WT, et al. Diabetes Care. 2014;37:912-921.
7. Sjostrom L, et al. N Engl J Med. 2004;351:2683-2693.
Q2. How is prediabetes managed?
Intervention Follow-up Period
Reduction in Risk of T2D
(P value vs placebo)
Antihyperglycemic agents
Metformin1
2.8 years 31% (P<0.001)
Acarbose2
3.3 years 25% (P=0.0015)
Pioglitazone3
2.4 years 72% (P<0.001)
Rosiglitazone4
3.0 years 60% (P<0.0001)
Weight loss interventions
Orlistat5
4 years 37% (P=0.0032)
Phentermine/topiramate6
2 years 79% (P<0.05)
Bariatric surgery7
10 years 75% (P<0.001)
Lifestyle modification should be used with all pharmacologic or surgical interventions.

Approach to the ManagementApproach to the Management
of Hyperglycemiaof Hyperglycemia
ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37. Figure 6.1; adapted with
permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

Management of DM
T1D T2D
• Use MDI or CSII insulin
– In children younger than 4
years, bolus insulin may be
given after, rather than before,
meals due to variable
carbohydrate intake
– Higher insulin-to-
carbohydrate ratios may be
needed during puberty
– Pubescent girls may require
20% to 50% increases in
insulin dose during menstrual
periods
• Lifestyle modification is first-
line therapy
• Metformin, alone or in
combination with insulin, is
approved by the FDA to treat
T2D in pediatric patients
• Rosiglitazone and glimepiride
have also been studied in
pediatric patients with T2D
81
Q16. How is a comprehensive care plan established in children and
adolescents?

ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S43. Figure 7.1;
adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S46. Figure 7.2; adapted with permission from Inzucchi SE,

“Niche” Drugs
• Colesevelam (Welchol)
- adjunct to lower A1c and LDL
- limited efficacy, cost
• Repaglinide (Prandin), Nateglinide (Starlix)
- may replace SU if sulfa allergy
- Prandin may be useful in CKD
• Acarbose (Precose), Miglitol (Glyset)
- limited efficacy, GI intolerance, cost
• Bromocriptine (Cycloset)
- limited efficacy? Will be marketed
• Salsalate
-older NSAID, may lower blood sugar, no
indication yet

Pramlintide-Synthetic Amylin
(Symlin)
• Amylin secreted by normal pancreas along
with insulin to regulate blood glucose
• Enhances Postprandial control. Used in
Type 1 and Type 2 patients
• Used as adjunct to insulin
• Available in pen injector
• Possible significant hypoglycemia

Beta-cell function declines as
diabetes progresses
Beta-cell
function (%)
Beta-cell decline exceeds 50%
by time of diagnosis
4-4-12 -8 0 8 12
0
50
100
75
25 Type 2 Diabetes
IGT
Years from diagnosis
Postprandial
Hyperglycemia
Diagnosis
Insulin
initiation
Beta-cell function decline over time
bovitz H. Diabetes Rev 1999;7:139-153.

Oral ClassOral Class MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCost
Biguanides
• Activates AMP-
kinase (?other)
• ↓ Hepatic glucose
production
• Extensive experience
• No hypoglycemia
• Weight neutral
• ? ↓ CVD
• Gastrointestinal
• Lactic acidosis
(rare)
• B-12 deficiency
• Contraindications
Low
Sulfonylureas
• Closes KATP
channels
• ↑ Insulin secretion
• Extensive experience
• ↓ Microvascular risk
• Hypoglycemia
• ↑ Weight
• Low durability
• ? Blunts ischemic
preconditioning
Low
Meglitinides
• Closes KATP
channels
• ↑ Insulin secretion
• ↓ Postprandial glucose
• Dosing flexibility
• Hypoglycemia
• ↑ Weight
• ? Blunts ischemic
preconditioning
• Dosing frequency
Mod.
TZDs
• PPAR-γ activator
• ↑ Insulin sensitivity
• No hypoglycemia
• Durability
• ↓ TGs (pio)
• ↑ HDL-C
• ? ↓ CVD events (pio)
• ↑ Weight
• Edema/heart failure
• Bone fractures
• ↑ LDL-C (rosi)
• ? ↑ MI (rosi)
Low
Table 1. Properties of anti-hyperglycemic agents

Oral ClassOral Class MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCost
α-
Glucosidase
inhibitors
• Inhibits α-glucosidase
• Slows carbohydrate
digestion / absorption
• No hypoglycemia
• Nonsystemic
• ? ↓ CVD events
• Modest ↓ A1c Mod.
DPP-4
inhibitors
• Inhibits DPP-4
• Increases incretin (GLP-
1, GIP) levels
• No hypoglycemia
• Well tolerated
• Angioedema / urticaria
• ? Pancreatitis
• ? ↑ Heart failure High
Bile acid
sequestrants
• Bind bile acids
• ? ↓ Hepatic glucose
production
• No hypoglycemia
• ↓ LDL-C
• Modest ↓ A1c
High
Dopamine-2
agonists
• Activates DA receptor
• Alters hypothalamic
control of metabolism
• ↑ insulin sensitivity
• No hypoglyemia
• ? ↓ CVD events
• Modest ↓ A1c
• Dizziness, fatigue
• Nausea
• Rhinitis
High
SGLT2
inhibitors
• Inhibits SGLT2 in
proximal nephron
• Increases glucosuria
•↓ Weight
• No hypoglycemia
• ↓ BP
• Effective at all stages
• GU infections
• Polyuria
• Volume depletion
• ↑ LDL-C
• ↑Cr (transient)
•FDA alert : ↑ DKA
High
Diabetes Care 2015;38:140-149;
Diabetologia 2015;58:429-442

InjectableInjectable
ClassClass
MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCost
Amylin
mimetics
• Activates amylin
receptor
• ↓ glucagon
• ↓ gastric emptying
• ↑ satiety
• ↓ Weight
• Modest ↓ A1c
• Injectable
• Hypo if insulin dose
not reduced
• Training requirements
High
GLP-1
receptor
agonists
• Activates GLP-1 R
• ↑ Insulin, ↓
glucagon
• ↓ gastric emptying
• ↑ satiety
• ↓ Weight
• No hypoglycemia
• ↓ Some CV risk
factors
• ? Pancreatitis
• ↑ Heart rate
• Medullary ca
(rodents)
• Injectable
High
Insulin
• Activates insulin
receptor
• Myriad
• Universally effective
• Unlimited efficacy
• ↓ Microvascular risk
• Hypoglycemia
• Weight gain
• ? Mitogenicity
• Injectable
• Patient reluctance
Variable
Diabetes Care 2015;38:140-149;
Diabetologia 2015;58:429-442

What is your current HbA1c?
8%
What is your target HbA1c?
Less than 7%
Current Diabetes Control: HbA1c or A1C
www.TuDiabetes.org

Insulin therapyInsulin therapy
• Insulin therapy aims to replicate the normal physiological
insulin response
• Insulin regimens should be individualized
– type of diabetes
– willingness to inject
– lifestyle
– blood glucose monitoring
– age
– dexterity
– glycaemic targets

Goals
Multiple Insulin Injection Therapy
I
N
S
U
L
I
N
I
N
J
E
C
T
I
O
N
Clinical Goals:
Elimination of ketosis.
Elimination of hyperglycemia and it’s symptoms.
Prevention of chronic complications.
Additional Goals:
Maintaining desirable weight.
Maintaining normal growth and sexual maturation.
Maintaining psychosocial well-being.
Achieving normal fertility and pregnancy.
Sustaining normal family and sexual life.
Control Goals:
HbA1c <7%.
Pre-meal SMBG 80-120 mg/dl (4.4-6.7 mmol/l).
Bed time SMBG 100-140 mg/dl (5.6-7.8 mmol/l).
No ketonuria.
Mean blood glucose level 120-160 mg/dl (6.7-8.9 mmol/l).

Address Concerns With Starting Insulin Therapy
1. Perceived failure to manage
diabetes (“My diabetes is
getting worse”)
2. Fear of injections (“The
injection will hurt”)
3. Taking insulin is too
complicated (“I am too busy
already; I don’t know I can fit
this in”)
4. Insulin will cause too many
lifestyle changes (“Using
insulin is a hassle and will
change my life”)
5. Insulin causes serious
complications (“If I start insulin, I
might go blind”)
6. Fear of hypoglycemia (“I am
afraid of having an insulin
reaction”)
7. Insulin causes weight gain (“I
don’t want to gain weight, I am
trying to lose weight”)
8. Insulin therapy is expensive “I
am already taking a lot of
medications; how can I afford to
buy more”)

Before Insulin
JL on 12/15/22 and 2
months later

Chemically, insulin is a small, simple protein. It consists of
51 amino acid, 30 of which constitute one polypeptide
chain, and 21 of which comprise a second chain. The two
chains are linked by a disulfide bond.
Source: Chance, R. and Frank B. - Research, development, production and safety of Biosynthetic Human Insulin.

• Type 1 diabetes
• Women with diabetes who
become pregnant or are
breastfeeding
• Transiently in type 2
diabetes in special
situations
• In type 2 diabetes,
inadequately controlled on
glucose-lowering medicines
(secondary failure)

Indications for Insulin Use in Type 2 Diabetes
o Pregnancy (preferably prior to pregnancy)
o Acute illness requiring hospitalization
o Perioperative/intensive care unit setting
o Postmyocardial infarction
o High-dose glucocorticoid therapy
o Inability to tolerate or contraindication to oral antiglycemic agents
o Newly diagnosed type 2 diabetes with significantly elevated
blood glucose levels (pts with severe symptoms or DKA)
o Patient no longer achieving therapeutic goals on combination
antiglycemic therapy

Advantages of Insulin TherapyAdvantages of Insulin Therapy
• Oldest of the currently available
medications, has the most clinical
experience
• Most effective of the diabetes medications
in lowering glycemia
– Can decrease any level of elevated HbA1c
– No maximum dose of insulin beyond which a
therapeutic effect will not occur
• Beneficial effects on triglyceride and
HDL cholesterol levels Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Disadvantages of Insulin TherapyDisadvantages of Insulin Therapy
• Weight gain ~ 2-4 kg
– May adversely affect cardiovascular health
• Hypoglycemia
– However, rates of severe hypoglycemia in
patients with type 2 diabetes are low…
 Type 1 DM: 61 events per 100 patient-yearsType 1 DM: 61 events per 100 patient-years
 Type 2 DM: 1-3 events per 100 patient-yearsType 2 DM: 1-3 events per 100 patient-years
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Balancing Good Glycemic Control withBalancing Good Glycemic Control with
a Low Risk of Hypoglycemiaa Low Risk of Hypoglycemia……
Hypoglycemia
Glycemic
control

Types of Insulin
• Beef
• Porcine
• Human Insulin
– Regular
– NPH (Neutral Protamine Hagedorn)
– 70/30
• Insulin Analogues
– Ultra Short Acting
– Long Acting

• The amino acid sequence for insulin is highly conserved in
mammals.
• Porcine insulin has only a single amino acid variation from the
human variety
• Bovine insulin varies by three amino acids.
• Both are active on the human receptor with approximately the
same strength.
• Non human insulins can cause allergic reactions in some
people, and human insulin replaced animal analogues

Stage 1 Insulin was extracted from the glands of
cows and pigs. (1920s)
Stage 2 Convert pig insulin into human insulin by
removing the one amino acid that distinguishes them
and replacing it with the human version.

Amino Acid Substitutons
A- chain
Position
B- chain Position
Source/
Type
A21 B3 B28 B29 B30 B31
And
B32
Human Asn Asn Pro Lys Thr
Aspart Asn Aspartic
acid
Lys Thr
Lispro Asn Lys Pro Thr
Glulisine Asn Lys Pro Glu Thr
Glargine Gly Pro Lys Thr Arg
Detemir Lys Myristic
acid
long-acting

Relative Insulin
Deficiency
Relative Insulin
Deficiency
Pre-diabetes and
Type 2 Diabetes
Pre-diabetes and
Type 2 Diabetes
Insulin
Resistance
Insulin
Resistance
Incretin DysfunctionIncretin Dysfunction
Insulin
Deficiency
Insulin
Deficiency
Type 1 DiabetesType 1 Diabetes
Critical role in both Type 1 and Type 2 diabetes
• Greatest potency of available therapies
• Demonstrated benefit – multiple clinical trials

Principles of Insulin Therapy
in T1D
• Starting dose based on weight
– Range: 0.4-0.5 units/kg per day
• Daily dosing
– Basal
• 40% to 50% TDI
• Given as single injection of basal analog or 2 injections of NPH
per day
– Prandial
• 50% to 60% of TDI in divided doses given 15 min before each
meal
• Each dose determined by estimating carbohydrate content of meal
• Higher TDI needed for obese patients, those with
sedentary lifestyles, and during puberty
Q5. How should glycemia in T1D be managed?
TDI = total daily insulin. 127

Insulin Regimens
• Insulin is required for survival in T1D
• Physiologic regimens using insulin analogs
should be used for most patients
128

Pharmacokinetics of Insulin
129
* Exhibits a peak at higher dosages.
† Dose-dependent.
NPH, Neutral Protamine Hagedorn.
Moghissi E et al. Endocr Pract. 2013;19:526-535. Humulin R U-500 (concentrated) insulin prescribing information. Indianapolis: Lilly USA, LLC.

Rosenstock J. Clin Cornerstone. 2001;4:50-61.
0 2 4 6 8 10 12 14 16 18 20 22 24
PlasmaInsulinLevels
Time (hr)
NPH (10–20 hr)
Regular (6–10 hr)
Ultralente (~16–20 hr )

Rosenstock J. Clin Cornerstone. 2001;4:50-61.
0 2 4 6 8 10 12 14 16 18 20 22 24
PlasmaInsulinLevels
Time (hr)
NPH (10–20 hr)
Regular (6–10 hr)
Ultralente (~16–20 hr )
Glargine (~24 hr)
Aspart, Lispro, Glulisine (4–5 hr)
Detemir
~18hr

Rates of Hypoglycemia for PremixedRates of Hypoglycemia for Premixed
vs. Long-Acting Insulin + OADvs. Long-Acting Insulin + OAD
Adapted from Janka et al. Diabetes Care 2005;28:254-9.
Mean number of confirmed hypoglycemic events
per patient-year in a 28-week study
0
1
2
3
4
5
6
Symptomatic Nocturnal Severe
Premixed insulin
Insulin glargine + OADs
5.73
2.62
1.04
0.51
0.05 0.00
Eventsperpatient-year
p=0.0009
p=0.0449 p=0.0702

Regular insulin
• Clear solution at neutral pH
• 0.4% zinc added-hexamers
• Phenol or cresol-prevent growth of
microorganisms
• Onset of action within 15-30 min after SC
• max activity-120 -150 min
• Action -6-8 hrs
• Insulin to be given 30-40 min prior to meals

NPH or isophane insulin
• At hagedorn university in 1940.
• Protamine added in 1:6 ratio to regular insulin
• Phosphate buffer for neutral ph
• Zinc ,cresol.
• Peak of action at 5-7 hrs
• Action lasts for 12-15 hrs.
• Bed time to control FBS.
• Cloudy.

Lente insulin
• Zinc in amounts 10 times to NPH
• Acetate as buffer
• Insoluble zinc insulin complexes
• Semilente---amorphous,biphasic absorption
• Ultralente—long acting crystalline suspension
• Can’t be mixed with regular insulin.

Premixed formulations
• 30:70
• 50:50
• 25:75
• Regular and NPH
insulin

Rapidly acting insulins—
insulin analogues
• Analogous to keep insulin in monomeric form
• Only change in aminoacid sequence
at a particular point.
• Action starts within 15 min after SC injection.
• Peaks at 60-90 min
• Over by 4 hrs
• Post prandial excursions curtailed
• No delayed hypoglycemia.

HumanHuman InsulinInsulin
PHEPHE
A-CHAINA-CHAIN
B-CHAINB-CHAIN
11
22
33
44
55
66
77
88
99
1010
1111
11
22
1313
1414
1515 1616 1717 1818
1919 22
00
2121
22
22
22
33
2424
2525
2626
22
77
2828
2929
11
22
33
44
55
66
77
88
99
1010 1111 11
22
1313 1414
1515
1616
1717
11
88
1919
2020
2121
SS
SS
SS
SS
SS
SS
VALVAL
ASNASN
GLNGLN
HISHIS
LEULEU
CYSCYS
GLYGLY
SERSER
HISHIS
LEULEU
VALVAL
GLUGLU
ALAALA LEULEU TYRTYR LEULEU VALVAL CYSCYS GLYGLY
GLUGLU
ARGARG
GLYGLY
PHEPHE
PHEPHE
TYRTYR
THRTHR
PROPRO
LYSLYS
THRTHR
GLYGLY
ILEILE
VALVAL
GLUGLU
GLNGLN
CYSCYS
CYSCYS
THRTHR
SERSER
ILEILE CYSCYS SERSER LEULEU TYRTYR
GLNGLN
LEULEU
GLUGLU
ASNASN
TYRTYR
CYSCYS
ASNASN
33
00
11
88
99
1010
22
33
44
55
SS
GLYGLY
SERSER
VALVAL
GLUGLU
Insulin LisproInsulin Lispro
PHEPHE
A-CHAINA-CHAIN
B-CHAINB-CHAIN
22
33
44
55
66
77
1111
1212
1313
1414 1515 1616 1717 1818 1919 2020
2121
2222
2323
2424
2525
2626
2727
2828
2929
11
66
77
88
99
1010 1111 1212 1313 1414
1515
1616
1717
1818
1919
2020
2121
SS
SS
SS SS
SS
VALVAL
ASNASN
GLNGLN
HISHIS
LEULEU
CYSCYS
HISHIS
LEULEU
VALVAL
GLUGLU
ALAALA LEULEU TYRTYR LEULEU VALVAL CYSCYS GLYGLY
GLUGLU
ARGARG
GLYGLY
PHEPHE
PHEPHE
TYRTYR
THRTHR
LYSLYS
PROPRO
THRTHR
GLYGLY
ILEILE
GLNGLN
CYSCYS
CYSCYS
THRTHR
SERSER
ILEILE CYSCYS SERSER LEULEU TYRTYR
GLNGLN
LEULEU
GLUGLU
ASNASN
TYRTYR
CYSCYS
ASNASN
3030
DiMarchi et al. Peptides-Chemistry and Biology 1992:26-28.
Howey et al. Diabetes 1994; 43:396-402.

Glu
Thr
Lys
Thr
Tyr Phe Phe Gly Arg
Glu
Gly
Cys
Val
Le
u Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
CysLeuHisGlnAsnValPheB1
Asn Cys
Tyr
Asn
Glu
Leu
Gln
Tyr
Leu
SerCysIleSerThrCys
Cys
Gln
Glu
Val
Ile
Gly
A21
B28B30
Asp
Pro
Asp

Long acting insulin
analogues
• Steady basal insulin levels
• Glargine –isoelectric at 7.4
• Clear and soluble at acidic ph
• Ppt after SC injection
• Action >24 hrs
• Detemir—fatty acid chain attached to it.

Vajo & Duckworth, 2000. Pharmacological Reviews, 52:1-9; Heinemann L et al. Diabetes Care 2000;23:644–649;
Hilgenfeld R et al. Diabetologia 1992;35[Suppl 1]:A193
These changes cause a shift in the isoelectric point from 5.4 in native insulin to 7.0 in
insulin glargine
NH2
COOHNH2
COOH
S
S S
S
S
A21[Gly]
B-chain
A-chain
S
B31[Arg]
B32[Arg]
Arg
extension
Asp
subtitution
• Formulated at acid pH—4.0 , Hexamers at pH-7.4

LysB29(N-tetradecanoyl)des(threonine)human insulin
Thr
Glu
Lys
ValPhe
Asn
Glu
Leu
Gln
Tyr
Leu
SerCysIleSerCys
Cys
Gln
Glu
Val
Ile
Gly
Tyr
CysAsnLys
Pro
Thr
Tyr
Phe
Phe
ArgGly
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
Cys
Asn Gln LeuHisB1
A21
A1
B29
C14 fatty acid
chain(Myristic acid)
Thr
Des-threonine myristic(mir) acid

levemir
Albumin binding: Makes Levemir therapy with a smooth
and peakless profile throughout the day

Premixed analogue
• Protamine insulin +rapidly acting analogues.

• Levemir FlexPen = identified by green push button
• NovoMix 30 FlexPen = identified by Blue push button
• NovoRapid FlexPen = identified by orange push button

Wash Hands Roll Bottle
Invert
bottle
Fill syringe with air
Withdraw cloudy
insulin

• Possible sites to inject insulin for Diabetes mellitus:
Abdomen
• quick insulin
absorption
Upper thigh + buttocks
• slow insulin
absorption

• Possible injections sites:
•Change injection sites on a
regular basis by rotating site
•Minimum distance of 3 cm
between two injection sites
•Minimum distance of 3 cm to
the navel

Strength of insulin
• 40 U /ml –most widely used
• WHO—all insulin across the globe to be U 100.
• Storage
• Refrigerated
• <2 and >30 °C
• Excess agitation avoided
• Used for > 1 month –may lose potency.
• Away from sunlight.

Insulin dose calculation
• Calculate total daily insulin TDI
• 0.5 *WEIGHT (KG) or sum of current doses
• Ex—60 kg---30U.
• Total meal time insulin—lispro,aspart,regular
• 60% 0f TDI
• 18U-----three divided doses—breakfast,lunch.dinner
• Total basal insulin—NPH,glargine,ultrlente
• 40% of TDI
• 12U---bed time insulin

If most AM fasting BG
>120 mg/dL
(>6.7 mmol/L)
Titrate until fasting glucose at target BG
• Use IDC regimen or increase 2 u
[or 4 u if FBG >180 mg/dl or 10 mmol/L] every 3-
7 days
• If dose reaches ~0.5 u/kg body weight, consider
adding mealtime insulin
If most AM fasting BG
<120 mg/dL
(<6.7 mmol/L) and
A1C remains above target
Test pre supper and bedtime
(or 2-hour post supper) and consider need for
mealtime insulin

If most BG >200 mg/dL (11.1
mmol/L)
Increase total insulin by 0.1 units/kg
Distribute equally between doses
If most BG <200 mg/dL (11.1
mmol/L)
Use titration guide to adjust
AM BG: adjust pre-dinner insulin dose
Pre-dinner BG: adjust pre-breakfast insulin
Adjust premixed insulin (RA 25/30% + BI 75/70%) based on the pre-breakfast (AM)
and pre-dinner BG
Mazze R, et al. Staged Diabetes Management Adult Quick Guide, 5th
Edition Revised, 2010
International Diabetes Center

If most BG >200 mg/dL
(11.1 mmol/L)
Increase total insulin by 0.1 units/kg
Add half to background
Distribute remaining half between mealtime doses
If most BG <200 mg/dL
(11.1 mmol/L)
Use titration guide to adjust:
• AM BG: adjust background
• Pre-lunch/dinner: adjust previous mealtime insulin
• If more than 40 mg/dL (2.2 mmol/L) pre- to 2 hr.
postmeal rise, increase mealtime insulin by 1-3
units
•Adjust basal (background) insulin based on the pre-breakfast (AM) BG
•Adjust bolus (mealtime) insulin based on the pre-meal BG
Mazze R, et al. Staged Diabetes Management Adult Quick Guide, 5th
Edition Revised, 2010

Pre prandial insulin dose
• INSULIN /CARBOHYDRATE ratio
• 1-1.5 U/10 gm of carbohydrate
• Supplemental or correcting insulin—1Uof
insulin for every 50mg/dl of glucose over
the preprandial glucose target.
• Ex
• A 60kg male has FBG 0f 250 mg/dl,desired
is 100mg/dl,the insulin dose is 60*(250-
100)/1500

Insulin dosage
• DKA
• Bolus dose—IV 0.1U/kg
• IM-0.3U/kg
• Then 0.1U/kg/hr
• Mild episodes of DKA—short acting insulin analogues
• IV regular insulin to be used in infusion until acidosis
resolves
• 0.05-0.1U/kg/hr.

BG
Below
70 mg/dL
(3.9 mmol/L)
Common Symptoms
 Weak, shaky, lightheaded
 Sweaty, clammy
 Irritability
 Tingling or numb lips
 Confusion
 Hungry

171
Classification
Blood
Glucose Level
(mg/dL)
Typical Signs and Symptoms
Mild hypoglycemia ~50-70
• Neurogenic: palpitations, tremor,
hunger, sweating, anxiety, paresthesia
Moderate
hypoglycemia
~50-70
• Neuroglycopenic: behavioral changes,
emotional lability, difficulty thinking,
confusion
Severe hypoglycemia <50*
• Severe confusion, unconsciousness,
seizure, coma, death
• Requires help from another individual
*Severe hypoglycemia symptoms should be treated regardless of blood glucose level.
Q6. How should hypoglycemia be managed?

Treatment of Hypoglycemia
172
Q6. How should hypoglycemia be managed?
Patient severely confused or
unconscious (requires help)
Patient severely confused or
unconscious (requires help)
o 15-30 gm of carbs ( 8 onz of juice,
2 crackers=10 carbs , glucose
tablets)
o RULE OF THUMB : 15 gm of
carbs will increased glucose levels
25-50 mg/dL
o Repeat glucose intake if SMBG
result remains low after 15 minutes
o Consume meal or snack after
SMBG has returned to normal to
avoid recurrence
o 15-30 gm of carbs ( 8 onz of juice,
2 crackers=10 carbs , glucose
tablets)
o RULE OF THUMB : 15 gm of
carbs will increased glucose levels
25-50 mg/dL
o Repeat glucose intake if SMBG
result remains low after 15 minutes
o Consume meal or snack after
SMBG has returned to normal to
avoid recurrence
Patient conscious and alertPatient conscious and alert
Hypoglycemia symptoms
(BG <70 mg/dL)
Hypoglycemia symptoms
(BG <70 mg/dL)
o 1 amp D50 or 1 mg
glucagon IM (repeat q
15 min )
o Patient should be taken
to hospital for
evaluation and
treatment after any
severe episode
o 1 amp D50 or 1 mg
glucagon IM (repeat q
15 min )
o Patient should be taken
to hospital for
evaluation and
treatment after any
severe episode
BG = blood glucose; SMBG = self-monitoring of blood glucose.

Insulin is released in response to varying blood glucose levels
and hypoglycemia does not occur
InsulinEffect
Basal Insulin
(~0.5-1.0 U/hr.)
‘Bolus’ Insulin
(Meal Associated)

BASAL INSULIN
• Suppress hepatic glucose
production (overnight and
intermeal)
• Prevent catabolism (lipid
and protein)
– Ketosis
– Unregulated amino
acid release
• Reduce glucolipotoxicity
BOLUS INSULIN
• Meal-associated CHO
disposal
• Storage of nutrients
• Help suppress inter-meal
hepatic glucose
production

Bolus vs Basal Insulin
• Bolus insulins
– Regular
– Humalog (lispro)
– NovoLog (aspart)
– Apidra (glulisine)
• Basal insulins
– NPH
– Lente
– Ultralente
– Lantus (glargine)
– Levemir (detemir) Combination insulins
— 70/30 and 50/50
— Humalog mix (75/25 or NPL)
— NovoLog mix (70/30 or NPA)

Basic Insulin Regimen: Split-
Mixed Regimen or Premix
• Does not
mimic normal
physiology
• Requires meal
consistency
• Snacking may
result in weight
gain
• Hypo- and
hyperglycemia
Regular
NPH
B DL HS B
Endogenous insulin
Hyperglycemia

Split Mixed Insulin (R/N)
R/NR/NR/NR/N
RegReg
NPHNPH
RegReg
NPHNPH
0
10
20
30
40
50
0 2 4 6 8 10 12 14 16 18 20 22 24
Time of DayTime of Day
SeruminsulinSeruminsulin(µU/mL)
Park Nicollet

InsulinEffect
B DL HS
Bolus insulin
Basal insulin
Basal-Bolus or Physiologic
Insulin Therapy
Endogenous insulin
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY:
Marcel Dekker, Inc; 2002:193

RA
RA
RA
Seruminsulin(mU/L)
Hours
RA RA RA Long-Acting
Glargine
0
10
20
30
40
50
0 2 4 6 8 10 12 14 16 18 20 22 24

B DL HS
InsulinEffect
Sensitizer Basal InsulinSecretagogue
Basal Insulin Regimen

Basic Insulin Regimen: Split-
Mixed Regimen or Premix
Regular
NPH
B DL HS B
Endogenous insulin

For pre mixed insulins(70/30 preparations)
Step1:First calculate the total daily starting requirement of
insulin;
body weight(kg)/2
eg, For a 60kg patient,total daily dose =30 units
Step 2:Then devide this dose into 3 equal parts;
10+10+10
Step 3:Give 2 parts in the morning and 1 part in the evening;
Morning=20U Evening=10 U

InsulinEffect
B DL HS
Bolus insulin
Basal insulin
Basal-Plus Insulin Therapy
Endogenous insulin

InsulinEffect
B DL HS
Bolus insulin
Inhaled Bolus Insulin
Therapy
Endogenous insulin

InsulinEffect
B DL HS
Bolus insulin
Basal insulin
Basal-Bolus or Physiologic
Insulin Therapy
Endogenous insulin

Fatty Meals---Rapid
Acting Insulin
TIME
INSULINACTIVITY
GLUCOSELEVELS
HYPERGLYCEMIA

1. Hedman CA et al. Diabetes Care 2001;24:1120-
1121 2. Home PD et al. Eur J Clin Pharm 1999;55:199-
201 3. Novo Nordisk, data on file
Time (min)
-60 0 60 120 180 240 300 360 420 480 540
Aspart 1,2
PlasmaInsulinLevels
Effect of Premixing on Rapid-
Acting Analog Properties
Tmax 49-53 min
70/30 NovoLog Mix 3
Tmax 2.4 hours
189

Clinical Secrets
• Plan target glucose goals
• Think in terms of basal and bolus insulin
• Typical ratio of basal to bolus is 50:50 or 60:40
• Correction doses are generally given before meals
• 1700 Rule: 1700/TDD = Glucose lowering/unit insulin
• Adjust basal insulin based upon FBS and bolus
insulin based upon preprandial values

Summary of Key Dose
Concepts for Type 1 Diabetes
Parameter Formula Usual Range
Basal insulin
requirements
None (weight
based 0.2-0.5
U/kg)
12-24 U/day
Bolus requirements
(empiric)
Basal dose ÷ 3 or
number of meals/d
5-10 U/meal
Insulin:CHO ratio CF x 0.33 ~15
Correction factor 1700 ÷ TDD 30-50
NOTE: These are approximations on starting a physiologic insulin regimen and
must be adjusted based upon SMBG valuesWednesday, January 20, 2016 191

Contributions of FBG and
PPG to Overall Glycemia
Adapted from Monnier, Lapinski, Colette: Diab Care Mar 2003, pg 881
PPG + FBG = HbA1c (%)
0
10
20
30
40
50
60
70
80
1 2 3 4 5
A1c Quintiles
Contribution(%)
(<7.3) (7.3-8.4) (8.5-9.2) (9.3-10.2) (>10.2)
PPG
FPG

Inhaled Insulin (Exubera)
• Uses powdered native
human insulin
– 1 and 3 mg blister
packs
 3mg Blister
 0.15U/Kg (~10U Reg)
(3) 1mg Blister

Inhaled Insulin (Exubera)
and OHA
*P < .001
Weiss, et al. Diabetes. 1999;48(suppl 1):A12.
10
9
8
7
5
Baseline
(0)
Follow-up
(12)
Oral Agents +
Inhaled Insulin
Oral Agents Alone
SU and/or Met
Baseline
(0)
Follow-up
(12)
−2.3%
*
Weeks
6
HbA1c(%)

FPG: Exubera vs SC
Insulin at End Point
Hollander PA, et al. Diabetes Care. 2004;27:2356-2362.
Data on file.
Exubera SC
Mean∆FPG(mg/dL)
-40
-35
-30
-25
-20
-15
-10
-5
0
Standard Intensive
Type 2 DM
194
163
203
190
201
167
209
207
152
132
158
149
Type 1 DM
On insulin

Inpatient Glucose Targets for
Nonpregnant Adults
Hospital Unit Treatment Goal
Intensive/critical care
Glucose range, mg/dL 140-180*
General medicine and surgery, non-ICU
Premeal glucose, mg/dL <140*
Random glucose, mg/dL <180*
196
Q3. What are glycemic treatment goals of DM?
ICU = intensive care unit.

Therapeutic Lifestyle
Changes
Weight loss
(for overweight and
obese patients)
Reduce by 5% to 10%
Physical activity
150 min/week of moderate-intensity exercise (eg, brisk walking) plus
flexibility and strength training
Diet
• Eat regular meals and snacks; avoid fasting to lose weight
• Consume plant-based diet (high in fiber, low calories/glycemic
index, and high in phytochemicals/antioxidants)
• Understand Nutrition Facts Label information
• Incorporate beliefs and culture into discussions
• Use mild cooking techniques instead of high-heat cooking
• Keep physician-patient discussions informal
197
Q4. How are glycemic targets achieved for T2D?

Diet
I
N
S
U
L
I
N
I
N
J
E
C
T
I
O
N
25 years male IBW 60 kgm
Carbohydrate (65%) 390
Protein (10%) 60
Fat (25%) 150
Carbohydrate 100 gm
Protein (10%) 15 gm
Fat (25%) 17 gm
Diet Carbohy. Protein Fat _
Arabian bread 30 gm --- ---
Cheese 5 gm 10 gm 10 gm
Honey 50 gm 2 gm 3 gm
Glass of milk 10 gm 5 gm 5 gm_
Total 95 gm 17 gm 18 gm
Protein (10%) 80
Fat (25%) 200
Carbohydrate 130 gm
Protein (10%) 20 gm
Fat (25%) 22 gm
Rice 80 gm --- 6 gm
chicken 5 gm 15 gm 12 gm
Salad 30 gm 4 gm 4 gm
Orange 10 gm --- ---___
Protein (10%) 40
Fat (25%) 100
Carbohydrate 65 gm
Protein (10%) 10 gm
Fat (25%) 11 gm
Tuna sandwich 45 gm 12 gm 10 gm
Apple 15 gm --- ---
Tea --- --- --- _
60 Kg X 30 kcal = 1800 kcal
Breakfast 600 kcal Lunch 800 kcal Dinner 400 kcal
The total calories intake depends on patients age and activity but have to
related to the desirable body weight.
Total daily calories = IBW X Estimated daily energyTotal daily calories = IBW X Estimated daily energy
Add 300 kcal/day during pregnancy.
Add 500 kcal/day during lactation.
Fibers, sweeteners, vitamins, and minerals.

Nutrition Guidelines for Patients
Taking Insulin
Guide to Starting and Adjusting Insulin for Type 2 Diabetes, © International Diabetes Center, 2008

Healthful Eating
Recommendations
Carbohydrate
Specify healthful carbohydrates (fresh fruits and vegetables, legumes, whole grains); target
7-10 servings per day
Preferentially consume lower-glycemic index foods (glycemic index score <55 out of 100:
multigrain bread, pumpernickel bread, whole oats, legumes, apple, lentils, chickpeas,
mango, yams, brown rice)
Fat
Specify healthful fats (low mercury/contaminant-containing nuts, avocado, certain plant
oils, fish)
Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and trans fat;
choose fat-free or low-fat dairy products
Protein
Consume protein in foods with low saturated fats (fish, egg whites, beans); there is no need
to avoid animal protein
Avoid or limit processed meats
Micronutrients
Routine supplementation is not necessary; a healthful eating meal plan can generally
provide sufficient micronutrients
Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 are not recommended
for glycemic control
Vitamin supplements should be recommended to patients at risk of insufficiency or
deficiency
200

Healthful Eating
Recommendations
Carbohydrate
Specify healthful carbohydrates (fresh fruits and vegetables, legumes, whole grains); target
7-10 servings per day
Preferentially consume lower-glycemic index foods (glycemic index score <55 out of 100:
multigrain bread, pumpernickel bread, whole oats, legumes, apple, lentils, chickpeas,
mango, yams, brown rice)
Fat
Specify healthful fats (low mercury/contaminant-containing nuts, avocado, certain plant
oils, fish)
Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and trans fat;
choose fat-free or low-fat dairy products
Protein
Consume protein in foods with low saturated fats (fish, egg whites, beans); there is no need
to avoid animal protein
Avoid or limit processed meats
Micronutrients
Routine supplementation is not necessary; a healthful eating meal plan can generally
provide sufficient micronutrients
Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 are not recommended
for glycemic control
Vitamin supplements should be recommended to patients at risk of insufficiency or
deficiency
201

Blood Pressure Targets
204
Q7. How should hypertension be managed?
Blood pressure
Individualize on the basis of age, comorbidities, and
duration of disease, with general target of:
Systolic, mm Hg ~130
Diastolic, mm Hg ~80
A more intensive goal (such as <120/80 mm Hg) should be
considered for some patients, provided the target can be safely
reached without adverse effects from medication.
More relaxed goals may be considered for patients with
complicated comorbidities or those experience adverse
medication effects.

Medical Complications of Obesity
207
NAFLD
Cardiovascular DiseaseCardiovascular Disease
Dismotility/disability
GERD
Lung function
defects
Osteoarthritis
Sleep apnea
Urinary incontinence
Prediabetic states
HypertensionDyslipidemia
PCOS
DiabetesDiabetes
CardiometabolicCardiometabolicBiomechanicalBiomechanical OtherOther
GERD, gastroesophageal reflux disease; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome.
Pi-Sunyer X. Postgrad Med. 2009;121:21-33.
Androgen
deficiency
Cancer
Gallbladder
disease
Psychological
disorders
Q13. How is obesity managed in patients with diabetes?

Diagnosis of Obesity and Staging of for
Management
• Diagnose obesity according to body mass index (BMI)
– Overweight: BMI 25-29.9 kg/m2
– Obese*: BMI ≥30 kg/m2
• Consider waist circumference measurement for patients
with BMI between 25 and 35 kg/m2
– Larger waist circumference = higher risk for metabolic
disease
• Men: >102 cm (40 in)
• Women: >88 cm (35 in)
• Evaluate patients for obesity-related complications to
determine disease severity and appropriate management
208
Q13. How is obesity managed in patients with diabetes?
208
*BMI 23-24.9 may be considered obese in certain ethnicities; perform waist circumference and use ethnicity-specific criteria in risk analysis.

Lipid Targets
209
Q8. How should dyslipidemia be managed?
Parameter
Treatment Goal
Moderate risk High risk
Primary Goals
LCL-C, mg/dL <100 <70
Non–HDL-C, mg/dL <130 <100
Triglycerides, mg/dL <150 <150
TC/HDL-C ratio <3.5 <3.0
Secondary Goals
ApoB, mg/dL <90 <80
LDL particles <1,200 <1,000
 Moderate risk = diabetes or prediabetes with no ASCVD or major CV risk factors
 High risk = established ASCVD or ≥1 major CV risk factor
 CV risk factors
ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; HDL-C = high density lipoprotein
cholesterol; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol.

Lipid Management
210
Q8. How should dyslipidemia be managed?
ApoB = apolipoprotein B; HDL-C = high density lipoprotein cholesterol; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein
cholesterol; TC = total cholesterol; TG = triglycerides.

Assessment of Diabetic
Nephropathy
212
Q9. How is nephropathy managed in patients with diabetes?
AER = albumin excretion rate; eGFR = estimated glomerular filtration rate; T1D = type 1 diabetes; T2D = type 2 diabetes.
• Annual assessments
– Serum creatinine to determine eGFR
– Urine AER
• Begin annual screening
– 5 years after diagnosis of T1D if diagnosed
before age 30 years
– At diagnosis of T2D or T1D in patients
diagnosed after age 30 years

Staging of Chronic Kidney Disease
213
Q9. How is nephropathy managed in patients with diabetes?
CKD = chronic kidney disease; GFR = glomerular filtration rate; NKF = National Kidney Foundation.
Levey AS, et al. Kidney Int. 2011;80:17-28.

Diabetic Neuropathy Evaluations and Tests
Foot inspection
Foot structure and deformities
Skin temperature and integrity
Ulcers
Vascular status
Pedal pulses
Amputations
Neurologic testing
Loss of sensation, using 1 and 10-g monofilament
Vibration perception using 128-Hz tuning fork
Ankle reflexes
Touch, pinprick, and warm and cold sensation
Painful neuropathy
May have no physical signs
Diagnosis may require skin biopsy or other surrogate measure
Cardiovascular
autonomic neuropathy
Heart rate variability with:
•Deep inspiration
•Valsalva maneuver
•Change in position from prone to standing
215
Q11. How is neuropathy diagnosed and managed in patients with diabetes?
DM = diabetes mellitus; T1D = type 1 diabetes; T2D = type 2 diabetes.

Diabetic Neuropathy Management
All neuropathies
• Prevent by controlling blood glucose to individual targets
• No therapies proven to reverse neuropathy once it is established
• May slow progression by maintaining optimal glucose, blood
pressure, and lipid control and using other interventions that reduce
oxidative stress
Painful neuropathy
• Tricyclic antidepressants, anticonvulsants, serotonin reuptake
inhibitors, or norepinephrine reuptake inhibitors
Large-fiber
neuropathies
• Strength, gait, and balance training
• Orthotics to prevent/treat foot deformities
• Tendon lengthening for pes equinus
• Surgical reconstruction
• Casting
Small-fiber
neuropathies
• Foot protection (eg, padded socks)
• Supportive shoes with orthotics if needed
• Regular foot inspection
• Prevention of heat injury
• Emollient creams
216
Q11. How is neuropathy diagnosed and managed in patients with diabetes?

Comprehensive Management of CV Risk
• Manage CV risk factors
– Weight loss
– Smoking cessation
– Optimal glucose, blood pressure, and lipid control
• Use low-dose aspirin for secondary prevention of CV
events in patients with existing CVD
– May consider low-dose aspirin for primary prevention of CV
events in patients with 10-year CV risk >10%
• Measure coronary artery calcification or use coronary
imaging to determine whether glucose, lipid, or blood
pressure control efforts should be intensified
217
Q12. How is CVD managed in patients with diabetes?
CV = cardiovascular; CVD = cardiovascular disease.

Statin Use
• Majority of patients with
T2D have a high
cardiovascular risk
• People with T1D are at
elevated cardiovascular
risk
• LDL-C target: <70 mg/dL
—for the majority of
patients with diabetes who
are determined to have a
high risk
• Use a statin regardless of
LDL-C level in patients
with diabetes who meet
the following criteria:
– >40 years of age
– ≥1 major ASCVD risk
factor
• Hypertension
• Family history of CVD
• Low HDL-C
• Smoking
218
Q12. How is CVD managed in patients with diabetes?
ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; HDL-C = high density lipoprotein cholesterol;
LDL-C = low-density lipoprotein cholesterol.

Obstructive Sleep Apnea
Risk Factors Treatment Options
• Obesity
• Male sex
• Neck circumference >44 cm
• Age
• Narrowed airway
• Family history
• Hypertension
• Alcohol or sedatives
• Smoking
• Weight loss
• Continuous positive airway
pressure (CPAP)
• Additional options
– Adjustable airway pressure
devices
– Oral appliances
– Surgery
• Uvulopalatopharyngoplasty
(UPPP)
• Maxillomandibular
advancement
• Tracheostomy
219
Q14. What is the role of sleep medicine in the care of the patient with
diabetes?

DM and Depression
248
Q22. How should depression be managed in the context of
diabetes?
• Screen all adults with DM for depression
– Untreated comorbid depression can have
serious clinical implications for patients with
DM
• Consider referring patients with depression
to mental health professionals who are
knowledgeable about DM

DM and Cancer
• Screen obese individuals with DM more frequently and rigorously for
certain cancers
– Endometrial, breast, hepatic, bladder, pancreatic, colorectal cancers
• Increased BMI (≥25 kg/m2) also increases risk of some cancers
– Strong associations: endometrial, gall bladder, esophageal , renal, thyroid,
ovarian, breast, and colorectal cancer
– Weaker associations: leukemia, malignant and multiple melanoma,
pancreatic cancer, non-Hodgkin lymphoma
• To date, no definitive relationship has been established between
specific hyperglycemic agents and increased risk of cancer or cancer-
related mortality
– Consider avoiding medications considered disadvantageous to specific
cancers in individuals at risk for or with a history of that cancer
249
Q23. What is the association between diabetes and cancer?

DM and Occupational Hazards
250
Q24. Which occupations have specific diabetes management
requirements?
• Commercial drivers at high risk for developing T2D
– Screen as appropriate
– Encourage healthy lifestyle change
• Be aware of management requirements and use
agents with reduced risk of hypoglycemia in
patients with occupations that could put others at
risk, such as (not inclusive):
– Commercial drivers
– Pilots
– Anesthesiologists
– Commercial or recreational divers

Somogyi Phenomenon
I
N
S
U
L
I
N
I
N
J
E
C
T
I
O
N
0
10
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Cause:
Counter regulatory hormones response
to hypoglycemia at med-night.
Increase in hepatic glucose production.
Insulin resistance because of the
Counter regulatory hormones.
Treatment:
Decrease pre-supper intermediate insulin.
Defer the dose to 9 PM.
Change or start pre-bed snack.
– Check BSL AT 3 :00 a.m
– Give long acting at 11:00 p.m so peak
comes later
– Reduce dose of night time insulin

Dawn Phenomenon
I
N
S
U
L
I
N
I
N
J
E
C
T
I
O
N
0
10
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Cause:
Less insulin at bed time.
More food at bed time.
Not using NPH at night.
Growth hormone surge at dawn
raises insulin requirement.
Treatment:
Use enough dose.
Reduce bed time snack.
• Add NPH pre-supper. Give long
acting insulin not before 11 :00 p.m
•May need to increase dose of
night time insulin

Pearls for practice
 Never try to control diabetes with oral hypoglycemic drugs /
insulin without first ensuring strict diet control.
 Always bring fasting sugar to normal before trying to control
post prandial / random blood sugar.
 Control any underlying infection/stressful condition vigorously.
 Keep meal timings regular with 6 hrs between the three meals.
 Do not inject NPH before 11 p.m.
 Keep number of calories during the meals same from day to day.
The quantity and quality of diet should be same at same timings.
 Do not use sliding scale to calculate the dose of insulin.
 Use proper technique to inject s/c insulin.
 Ensure proper storage of insulin.

Case---History
25 year old student comes to clinic for management
of type 1 diabetes. He was diagnosed
approximately 3 years ago and has been managed
with twice daily NPH insulin and lispro. He is
frustrated because his glucose values fluctuate
considerably, and he is having multiple episodes
of hypoglycemia.
His most recent A1C returned 7.8%.

Case---Continuous
Monitoring

Case Study--History
His current insulin regimen consists of 16 U of NPH plus 5 to
15 U of lispro prior to breakfast and 12 U of NPH with a
similar amount of lispro prior to supper. He would give
correction doses of lispro prior to lunch, bedtime and
occasionally at 2-4 AM. If he was ‘low’, he would eat
carbohydrate and not take lispro.
His home glucose log documented testing 4 to 5 times a day
with values ranging from 40 to 500 mg/dl.
How should his management be approached?

Case Study--Approach
• Set a reasonable goal for glycemic control
– Initial goal was to avoid hypoglycemia (glucose
targets 120-150 mg/dL)
• Trouble-shoot the insulin regimen
– Which type of insulin and which injection is
doing what?
– Good luck doing it with this patient!

• Variables with injected insulin:
– Type of insulin and site of injection
– Type of food and gastric emptying
– Remembering to take injections
– Accuracy of HGM
• Designing an insulin regimen
– Think in terms of basal and bolus

• We opted to use glargine as the basal
insulin and lispro as the bolus insulin
• Dose calculations:
– TDD: 48 to 73 U
– Basal (as NPH): 16+12=28 U
– Glargine: 28 x 0.8=22.4 U
CURRENT REGIMEN
16/10 and 12/10 (N/H)
TDD≈48 U/day
PLUS up to 25 U H/D

• Usual insulin regimens are 50:50 or 60:40
basal:bolus
– TDD: 48 to 73 U
– Glargine: 22 U
– Bolus: ~ 22 U (50:50 Rule)
• Per meal 22/3= 7.3 U/meal
• Designed regimen: Glargine 22 U/HS; lispro 7 U
BEFORE EACH MAJOR MEAL

• Correction doses (‘sliding scale’)
– 1700 Rule (some modify this as the 1500 Rule
or the 1800 Rule)
– 1700/TDD = Expected amount of glucose
lowering per unit of insulin
• Our patient
– 1700/44 = 38 ∴ 1 U insulin would lower his
glucose 38 mg/dl

• Our goal glucose is ~ 150 mg/dL
• Our patient is instructed to:
– Take 22 U glargine at bed time (or ~ 10:00 PM)
– Start with 7 U of lispro before meals
• For every 50 mg/dL glucose is above 150, add 1 U lispro or
for every 50 below 150, subtract 1 U lispro
– Have the patient monitor and adjust the regimen based
upon results of HGM

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