Diabetes Mellitus

Abdullah Al-dahbali, MPharm, PhD

 Introduction
• Diabetes Mellitus (DM) is a heterogeneous group of
metabolic disorders characterized by
– hyperglycemia
– abnormalities in carbohydrate (CHO), fat, and protein
metabolism
• It results from defects in insulin secretion, insulin
sensitivity, or both
• Chronic complications correlate with sustained,
uncontrolled hyperglycemia, and include
– microvascular (retinopathy, neuropathy, nephropathy)
– macrovascular (CHD, stroke, peripheral vascular disease)
Dr. Abdullah Al-dahbali 2
Insulin Physiologic Functions & CHO Metabolism
• Postprandially, glucose (via GIT incretin hormones glucagon-
like peptide-1 (GLP-1) and glucose-dependent insulinotropic
peptide (GIP)) stimulates Bolus insulin secretion
–promotes uptake of dietary glucose, fatty acids (FF) & amino acids & their
conversion to storage forms (glycogen, proteins & TG) in liver, muscles &
adipose tissue
• Between meals & during the night, there is a Basal insulin
secretion
–inhibits hepatic glucose production by suppressing glucagon & its effects
(e.g. gluconeogenesis)
–Prevents lipolysis (breakdown of TG in adipose tissue to FF)
• In fasting state, insulin counter-regulatory hormones
(norepinephrine, glucagon) produce glucose (for the brain)
from the storage forms
Dr. Abdullah Al-dahbali 3
 Pathophysiology
DM1 DM2
• Due to absolute insulin deficiency • Due to both insulin resistance &
• Develops in childhood or early adulthood relative insulin deficiency
• Immune-mediated destruction of
• Insulin resistance leads to
pancreatic β-cells
– ↑hepatic glucose production
– ↓skeletal muscle uptake of glucose
– Macrophages &T lymphocytes, with
– ↑lipolysis & free FF production
circulating autoantibodies to various β-
– ↑insulin secretion by β-Cells
cell antigens (e.g. islet cell antibody,
• Insulin deficiency results from
insulin antibodies)
progressive exhaustion of β-cells &
• These immune markers present for up to 9- contributes to worsening of blood
13 years before clinical Sx appear glucose control over time
• Hyperglycemia occurs when 80%-90% of β- • occurs when diabetogenic lifestyle
cells are destroyed (↑ calories, ↓ exercise, obesity) is
• There is a transient remission (honeymoon superimposed upon a susceptible
phase) after the initial hyperglycemia,
genotype (genetic predisposition)
followed by established disease with • ↓incretins effect on insulin
associated risks for complications & death
secretion Dr. Abdullah Al-dahbali 4
 Causes of DM
• Autoimmune (DM1)
• Environmental with genetic predisposition (DM2)
• Uncommon causes (1%-2%)
– Endocrine disorders (e.g., acromegaly, Cushing’s
syndrome), gestational diabetes mellitus (GDM)
– Diseases of the exocrine pancreas (e.g. pancreatitis)
– Medications (e.g. glucocorticoids, pentamidine, niacin,
α-interferon)
Dr. Abdullah Al-dahbali 5
 Clinical Presentation
DM1 DM2
• Lethargy • Often asymptomatic
• Polyphagia, Polyuria, • Diagnosed during a medical check-
up
Polydipsia
• May present with already-
• Nocturia
developed complications
• Significant weight loss
– DM with complications is called
• Blurred vision the Metabolic Syndrome
• Ketonemia, ketonuria & (Syndrome X)
ketoacidosis • At the time of Dx
• ↑ glycosylated hemoglobin – Lethargy
(HbA1C) – Polyphagia, Polyuria, Polydipsia
• Recurrent infections (URT, skin, – Nocturia
vaginal) – ↑ HbA1C
– Weight loss is not common
Dr. Abdullah Al-dahbali 6
 Comparison
DM1 DM2
• Young age • Older age
• Acute & static • Chronic & progressive
• Ketosis prone • Ketosis resistant
• Family history 10% • Family history > 30%
• Insulin treatment mandatory • Insulin treatment optional
• Patients usually lean • Patients usually obese

Dr. Abdullah Al-dahbali 7

 Criteria for the Diagnosis of DM
–Classic DM Sx (polyuria, polydipsia, and unexplained weight loss
plus
Random (Casual) Plasma Glucose (RPG, RBS) ≥200 mg/dL (11.1 mmol/L)
which is unexplained otherwise
OR
–Fasting (No caloric intake for at least 8 hrs) Plasma Glucose (FPG,
FBS) ≥126 mg/dL (7.0 mmol/L) which is unexplained otherwise
OR
–2-hrs postload plasma glucose ≥200 mg/dL (11.1 mmol/L) during
Oral Glucose Tolerance Test (OGTT) which is unexplained otherwise
• In OGTT, the person drinks 75 g glucose (load) in water after 8 hrs fasting
• If OGTT is positive for DM, the test should be repeated in a different day

• The hyperglycemia should be unequivocal, otherwise these criteria

should be confirmed by repeat testing on a different day
Dr. Abdullah Al-dahbali 8
 Screening for DM2
• Should be performed every 3 yrs beginning at age of 45 yrs
– earlier & more frequent if a risk factor presents
• Risk factors include family history, obesity, signs of insulin resistance
• The recommended screening test is a FPG test (Normal is <100 mg/dL)
• Impaired FPG is defined as FPG of 100-125 mg/dL
• Impaired glucose tolerance is diagnosed when the 2-hrs postload glucose
of the OGTT is between 140 &199 mg/dL
• Impaired FPG & impaired glucose tolerance describe patients
whose plasma glucose levels are higher than normal, but are not
diagnostic of DM
– These disorders are risk factors for developing DM, and are associated with
insulin-resistance syndrome (sometimes called glucose toxicity)
• Pregnant women should undergo risk assessment for gestational DM at
their first prenatal visit & proceed with glucose testing if
– Having DM
– Having a risk factor for DM Dr. Abdullah Al-dahbali 9
 Treatment- Goals & Tools
1) Improving patient’s 2) Preventing acute
quality of life complications (ketoacidosis
& hyperosmolar comas) &
– By ameliorating Sx of chronic complications
hyperglycemia 3) Delaying onset &
• Glucose <110 mg/dL preprandial progression of complications
& <180 mg/dL postprandial
– By maintaining euglycemia
– At beginning, preprandial
• HbA1C 4%-6% (??)
glucose <180 mg/dL is accepted
– Along with aggressive
– By preventing treatment- management of other CVD risk
related hypoglycemia factors
• Glucose >70 mg/dL preprandial • Tools include
• HbA1C 6.5%-7% – medical nutrition therapy (MNT)
– By preventing/ameliorating – drugs (insulin & oral
other treatment-related hypoglycemics (OHG) & others)
adverse effects – aerobic exercise
Dr. Abdullah Al-dahbali 10
 Treatment- Nonpharmacologic
1) Medical Nutrition therapy
 moderate CHO, low saturated fat, all essential vitamins and
minerals
2) Aerobic Exercise
 150min/wk moderate exercise(50%–70% max HR), but no
more than 2 days between activity
 Resistance/strength training is ≥ 2×/wk if no retinopathy
3) Life Style Modifications

Dr. Abdullah Al-dahbali 11

 Insulin Types & their Pharmacokinetic
Properties (after SC Injections)
Insulin Type Onset (hr) Peak (hr) Duration (hr) Appearance
Rapid-Acting, RAI
(Lispro, 15-30 min 30–90 min 3–5 Clear
Aspart, Glulisine)
Technosphere inhaled
5-10 min 45-60 min ~3 Powder
Insulin (Rapid-Acting)
Regular (Short-Acting,
0.5–1 2–3 5–8 Clear
SAI)
NPH (Intermediate-
2–4 4–12 12–18 Cloudy
Acting, IAI)
Glargine (Long-Acting, No pronounced
1.5 20–24 Clearb
LAI) peak
Detemir (Long-Acting,
3–8 Relatively flat 14-24 Clearb
LAI)
Degludec (Long-Acting,
~2 Relatively flat 30-36 Clearb
LAI)
bShould NOT be mixed with other insulins or administered IV. Some patients require twice-
daily dosing. Dr. Abdullah Al-dahbali 12
 Initiating Insulin Therapy in DM1 (See also PDF file)

• Start empirically with a total •Bolus times must match the pt’s meal
daily dose (TDD)=0.3-0.6 U/kg pattern (amounts (a) & times (b))
–Divide this TDD between the Basal a)For time matching, RAI (15 min.), SAI (30
& the Bolus components (50% each) min.) before each meal
• TDD to be administered as b)For amount matching, calculate
insulin-to-CHO ratio using the “500”
either 1) or 2) below Rule (RAI)/ or “450” Rule (SAI)
• Pramlintide-added if erratic – Ex: TDD=50 Unit. Thus, “500”/50= 10 g CHO
postprandial control will be covered by each Unit RAI
– Thus, pt must do CHO Counting
1)BOLUS-BASAL INSULIN THERAPY
(BBIT, physiologic)- panels C & D – Examples of servings that (per each) contain 15
g CHO include 1 fruit, 1/2 cup juice, 1 cup milk,
•BBIT attempts to mimic normal insulin 1/2 cup ice cream, 2 cookies, 3 sugar cubes
physiology (to achieve ~ normal blood
glucose throughout the day) to allow – a typical start is 1 unit insulin/15 g CHO, then
patient to live as a normal life as possible adjust based on postprandial glucose level
•Basal component (50% of TDD) to be •Use BBIT w caution if autonomic or
administered as LAI (OM, ON or both) counter-regulatory insufficiency (e.g. β-
•The remaining 50% of TDD to be blocker, CAD), alcoholics, nonadherence
administered as Boluses of RAI or SAI
before each meal •Panel D is Insulin Infusion Pump (RAI)
Dr. Abdullah Al-dahbali
•Blood glucose to be monitored >3x/day
 Initiating Insulin Therapy in DM1… Cont’ (See also PDF file)

2)TWICE OR THRICE DAILY INSULIN – If the 2nd IAI dose is taken at

THERAPY (TDIT)- panels A & B bed time (panel B), it is then
the Thrice Daily Insulin
–The 1st dose (0.67% of TDD) before breakfast Therapy (3DIT)
a) 33% of 1st dose as RAI or SAI (bolus component) to prevent
•useful for pts with
post-breakfast hyperglycemia +
troublesome nocturnal
b) 67% of 1st dose as IAI (basal component throughout
daytime) & to prevent post-lunch hyperglycemia
hypoglycemia & morning
hyperglycemia
–The 2nd dose (0.33% of TDD) before dinner
a) 50% of 2nd dose as RAI or SAI (bolus component) to take
– 3DIT shifts nocturnal
care of post-dinner hyperglycemia) + hypoglycemia to around 7
b) 50% of 2nd dose as IAI (basal component throughout night am (breakfast time)
time & to take care of any night snack –residual effect of bedtime
–Disadvantages of TDIT (because IAI is NPH insulin) NPH in 3DIT prevents
morning hyperglycemia
• NPH has a peak, thus it does not provide a real basal
component, thus it does not mimic the physiology – If a patient is switched from
• Patient MUST eat lunch ON TIME, otherwise hypoglycemia SAI to RAI in TDIT, IAI doses
would result from pre-breakfast NPH may have to be increased to
• Risk of nocturnal hypoglycemia (around 3 am) from the peak minimize preprandial
of pre-dinner NPH dose unless an evening snack is taken
hyperglycemia
Dr. Abdullah Al-dahbali 14
 Self-Monitored Blood Glucose (SMBG) & Interpretations
Test Time Target Insulin Dose Target Meal/Snack
Prebreakfast Predinner/bedtime IAI- or basal insulin Bedtime snack
(fasting) (daily)
Prelunch (daily) Prebreakfast RAI/SAI Breakfast/midmorning
snack
Predinner (daily) Prebreakfast IAI and/or prelunch RAI or Lunch/midafternoon
SAI snack
Bedtime (daily) Predinner RAI or SAI Dinner
2-hrs Premeal RAI or SAI Preceding meal or snack
postprandial
3 AM or later (3 Predinner IAI or basal insulin if given in amDinner/bedtime snack
times weekly)
•Assuming normal meal pattern, time matching, adherence, accurate measurement & reporting.
•Interpret SMBG in conjunction with other parameters such as HbA1c & laboratory BGLs.
•IF PREBREAKFAST GLUCOSE IS HIGH, CONSIDER THE FOLLOWING:
Reactive hyperglycemia (Somogyi effect). Hypoglycemia @3am is a consistent
finding that leads to “glucotoxicity”. Treat by correcting the 3am hypoglycemia
If no hypoglycemia @3am, waning of morning basal insulin or the Dawn
phenomenon are other possibilities. Treat by ↑or shifting basal dose to the night.
•Whenever glucose is high, consider reactive hyperglycemia (excessive insulin doses).
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 Patient Education
• DM- Complications • Self-testing & Interpretation
• Hyperglycemia- S/Sx • Foot Care
• Hypoglycemia- S/Sx & treatment – Daily inspection
• Ketoacidosis- S/Sx – wearing well-fitted shoes
– avoiding self-care of ingrown toenails,
• Exercise- Effect on glucose level & corns, or athlete's foot
insulin dose – see a podiatrist
• Diet- CHO Counting • Sick Day Management
• Insulin • Other Risk Factors for CVD
– Types, Onset, Peak & Duration times
– Mixing, measuring & Administration
• Importance of Ophthalmologic &
Proteinuria Check-up
– Storage, Stability
• Importance of Immunizations
• Goals & Parameters & their Targets

At initiation of therapy, each dose of prandial insulin should be reduced by

30% to 50% to prevent hypoglycemia, along with monitoring of postprandial (2
hrs after meal) glucose level in the blood
Dr. Abdullah Al-dahbali 16
Selecting Insulin Injection Sites

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 Hypoglycemia
S/Sx Management
• At <60 mg/dL, may not be • Ingestion of 15 g of a simple CHO
symptomatic (240 mL orange juice/milk, 4
glucose tablespoons)
• At <40 mg/dL, symptomatic • Repeat in 15 min. if glucose
– Sweaty palms & generalized remains <70 mg/dL or if patient is
sweating symptomatic
– tremor, hunger, confusion & • Follow with a complex CHO snack if
anxiety it's not a meal time
– Combativeness & poor judgment • If patient is unconscious
• At <20 mg/dL – Glucagon 1 mg SC, IM, or IV (mean
response time, 6.5 min), OR
– Seizures & coma
– Glucose 25 g IV (dextrose 50%, 50
• Nocturnal hypoglycemia mL; mean response time, 4 min)
– nightmares, restless sleep • Continue monitoring blood glucose
– morning headache & “hangover” • The key is recognition & prevention
– But maybe asymptomatic – Early Sx
– Causes
Dr. Abdullah Al-dahbali 18
 Exercise in DM
• Exercise in insulin deficiency: • Replenishment of glycogen
– Hyperglycemia due to ↑hepatic stores may continue for 12 hrs
glucose output without glucose after exercise
utilization – SMBG & adjust insulin & diet to avoid
– Thus, avoid exercise if BGL >300, or hypoglycemia (esp. in DM2)
>250 + ketosis
• Avoid injecting RAI into exercising
• Exercise in insulin excess: muscles
– Hypoglycemia due to ↓hepatic
glucose output &↑muscular glucose • Regular exercise is advantageous
utilization. Thus, – ↑tissue sensitivity &↓insulin needs
• Eat 10–20 g CHO before exercise if
BGL ≤normal(≤100) before
exercise, and have CHO readily
available during & after exercise
• Delay insulin till after exercise
• Avoid exercise at peak insulin
Dr. Abdullah Al-dahbali 19
times
 Sick Day Management
Case: A 32-year-old woman with DM1 has Management:
been well controlled on basal-bolus regimen 1)Plenty of fluid (½ cup water or soup/h) &
(four injections daily) for the past 6 months. caloric intake (50 g CHO Q 4 hrs)
However, 2 days ago, she began to develop
2)Continue basic dose of insulin even if no
S/Sx consistent with the flu. This has made
eating
her anorexic & nauseated, & now she has
begun to vomit. Consequently, her food 3)SMBG & urine ketones Q 3-4 hrs
intake has been minimal. 4)Calculate (by Rules?!!) & give supplemental
1) Because R.D. is not eating at this time, RAI or SAI to achieve a reasonable BGL (e.g.
should she discontinue her insulin? 150)
• Acute illnesses ↑insulin requirements even 5)Seek medical attention if:
if food intake↓ or diminished – BGL >240 after 2-3 supplemental insulin
– Thus, DM1 pts should NOT stop or doses, or
decrease their insulin, otherwise diabetic – high ketonuria , or
ketoacidosis will occur – vomiting or diarrhea > 6 hrs, or
– S/Sx of ketoacidosis:
• polyuria, polydipsia, dehydration,
ketonuria, fruity breath
Dr. Abdullah Al-dahbali 20
The Ominous Octet & Drugs Used in DM2

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 Drugs Used in DM2
Drug
(↓HbA1c/↓FBG%) Advantages Disadvantages CIs Instructions
Metformin No hypoglycemia,GI upset, long titration Lactic W food, start low &
(1.5–1.7/50–70) No weight gain, time, Big& frequent dosing Acidosis orgo slow, XR
↓Lipids, cheap its risk
factors
Acarbose (0.5-1) GI upset, long titration W food, start low &
time, big & frequent dose go slow, monitor LFT
TZDs No hypoglycemia,Weight gain, costly, HF, severe Monitor LFT, Lipids
(0.8–1.5) less failure (slow edema, fluid retention, liver
decline of ß- slow onset, hepatotoxic disase
cells), OD
SUs (1.5– OD, cheap, rapid Hypoglycemia, GI upset, Severe start low & go slow,
1.7/50–70) onset, effective weight gain liver No meal skipping,
disease ?? take 30’ before meal

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 Drugs Used in DM2… Cont’
Drug (↓HbA1c/↓FBG%)
Advantages Disadvantages CIs Instructions
DPP4 Inhibitors (0.8)- Safe in renal hypoglycemia Skip if meal
Sitagliptin, Saxagliptin, failure (Lina), skipped
Linagliptin, Alogliptin HF
Glinides (1.7)- PO, no Hypoglycemia, weight gain, Before meal, skip if
Nateglinide & regular meal DDI w Nateg.: Gemfibrozil, meal skipped
Repaglinide Trimethoprim
GLP-1RA- Exenatide weight loss GI upset, parenteral SC BD Before meal
(0.9)
GLP-1RA- Exenatide XR SC once weekly
(1.6)
GLP-1RA- Liraglutide SC OD
GLP-1RA-Albiglutide SC OD
GLP-1RA- Dulaglutide SC once weekly
Bromocriptine-DA2 ↑protein bound, nausea, Migraine, within 2 hrs after
agonist (0.1–0.5) psychosis, dizzy, headache lactation waking-up, w food

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