EPIDEMIOLOGY

Top 10 countries for number of adults with diabetes

(20-79 years) and their healthcare expenditure, 2017
EPIDEMIOLOGY
 Epidemiology
• The increasing prevalence of DM is partly caused by three
influences:
Lifestyle: A sedentary lifestyle coupled with greater
consumption of high-fat, high-carbohydrate foods, and larger
portion sizes
Ethnicity: Native Americans, Hispanic Americans, Asian
Americans, African Americans, and Pacific Islanders.
Age: As the population ages, the incidence of T2DM is expected
to increase
 Epidemiology

Total number of adults with diabetes (20-79 years)

 Classification of Diabetes
• The vast majority of diabetic patients are classified into one
of two broad categories:
Type 1 diabetes caused by an absolute deficiency of insulin or
~65% of pediatric patients with DM; 5 – 10% of adults with DM.
Type 2 diabetes defined by the presence of insulin resistance
with an inadequate compensatory increase in insulin secretion.
~35% of pediatric patients with DM; 90% to 95% of adults with DM.
 Etiologic Classification of DM
1. Type 1 diabetes (β-cell destruction, usually leading to absolute
insulin deficiency)
Immune mediated
Idiopathic

2. Type 2 diabetes
Insulin resistance with relative insulin deficiency
Insulin secretory defect with insulin resistance

3. Other specific types

Genetic defects of β-cell function
Diseases of the exocrine pancreas (pancreatitis, trauma, pancreatectomy,
neoplasia, cystic fibrosis)
Endocrinopathies (Acromegaly, cushing’s syndrome, glucagonoma,
pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma)
Etiologic Classification of DM

3. Other specific types, Continued

Drug- or chemical-induced: pentamidine, nicotinic acid,
glucocorticoids, thyroid hormone, β-adrenergic agonists,
thiazides, phenytoin, interferon alpha
4. Gestational diabetes mellitus (GDM)
 Pathogenesis
Type 1 DM
• Type 1 DM results from pancreatic β-cell failure with
“absolute” deficiency of insulin secretion.
Immune-mediated destruction of pancreatic β cells,
Unknown or idiopathic processes (rare).
• There often is a long preclinical period of immune-mediated
β-cell destruction later followed by onset of hyperglycemia
when 80% to 90% of the β cells have been destroyed.
• Occasionally there is a period of transient remission called
the “honeymoon” phase
The natural history of the β-cell defect in
type 1DM
 Pathogenesis
• The autoimmune process is mediated by macrophages and
T lymphocytes with circulating autoantibodies to various β-
cell antigens.
• The most commonly detected antibody associated with
type 1 DM is the islet cell antibodies (ICA)
• β-Cell autoimmunity may precede the diagnosis of type 1
DM by up to 9 to 13 years.
• Autoimmunity may remit in some individuals, or can
progress to absolute β-cell failure in others.
• Other autoimmune disorders frequently associated with
type 1 DM include Hashimoto’s thyroiditis, Graves’ disease,
Addison’s disease, vitiligo, and celiac sprue.
 Pathogenesis
• The autoimmune destruction of pancreatic β-cell function
results in hyperglycemia due to an absolute deficiency of
insulin.
• Insulin lowers blood glucose (BG) by a variety of
mechanisms, including stimulation of tissue glucose
uptake, suppression of glucose production by the liver, and
suppression of free fatty acid (FFA) release from fat cells.
• The suppression of FFAs plays an important role in glucose
homeostasis.
• Increased levels of FFAs inhibit the uptake of glucose by
muscle and stimulate hepatic gluconeogenesis
Pathogenesis
 Pathogenesis
Normal Metabolism
• In the fasting state:
Glucagon is produced by pancreatic α cells to:
Oppose the action of insulin and
Stimulate hepatic glucose production and
glycogenolysis.
85% of glucose production is derived from the liver, and the
remaining is by the kidney.
75% of total body glucose disposal takes place in brain, neurons,
and others.
Non–insulin-dependent tissues
The remaining 25% of glucose metabolism takes place in the liver
and muscle
Insulin dependent tissues.
 Pathogenesis
• In the fed state,
Carbohydrate ingestion increases the plasma glucose
concentration and
Stimulates insulin release from the pancreatic β cells.
• The resultant hyperinsulinemia
(a) Suppresses hepatic glucose production,
(b) Stimulates glucose uptake by peripheral tissues,

(c) Suppresses glucagon release (in conjunction

with incretin hormones).
The majority (80 to 85%) of glucose is taken up by muscle, with
only a small amount (4 to 5%) being metabolized by adipocytes
 Pathogenesis
Type 2 Diabetes
• Individuals are characterized by multiple defects including
(a) Defects in insulin secretion;
(b) Insulin resistance involving muscle, liver, and adipocyte;
(c) Excess glucagon secretion;
(d) Glucagon-like peptide-1 (GLP-1) deficiency and possibly
resistance
 Pathogenesis
Impaired Insulin Secretion
• The pancreas in people with a normal-functioning β cell is able
to adjust its secretion of insulin to maintain normal plasma
glucose levels.
• In nondiabetic individuals, insulin increases in proportion to
the severity of the insulin resistance and plasma glucose
remains normal.
• Impaired insulin secretion is a hallmark finding in T2DM.
• People with T2DM lose 5% to 7% of β-cell function per year of
diabetes.
• The reasons for this loss are likely multifactorial including (a)
glucose toxicity; (b) lipotoxicity; (c) insulin resistance; (d) age;
(e) genetics; and (f) incretin deficiency.
 Pathogenesis
Incretins
• In the type 2 diabetic patient, decreased postprandial insulin
secretion is due to both
Impaired pancreatic β-cell function and
Reduced stimulus for insulin secretion from gut hormones.
• Increased insulin secretion in response to an oral glucose
stimulus: “the incretin effect”
• GLP-1 and glucose-dependent insulinotropic polypeptide
(GIP), are responsible for over 90% of the increased insulin
secretion seen in response to an oral glucose load.
• Both hormones are rapidly inactivated by the enzyme
dipeptidyl peptidase-4 (DPP-4)
• In type 2 diabetic patients, this “incretin effect” is blunted
 Pathogenesis
Insulin Resistance
• Liver:
Fasting hyperglycemia
Increase in fasting hepatic glucose production
Postprandial hyperglycemia
From the diet and
From continued glucose production from the liver.
• Peripheral (Muscle)
Impaired intracellular insulin signaling: insulin resistance
 Pathogenesis
• Peripheral (Adipocyte)
Insulin resistance
• Lipolysis: release of FFAs from the adipocyte
• Gluconeogenesis indirectly through glycerol and
FFAs
 CLINICAL PRESENTATION
Characteristic Type 1 DM Type 2 DM
Age <30 years >30 years
Onset Abrupt Gradual
Body habitus Lean Obese or history of obesity
Insulin resistance Absent Present
Autoantibodies Often present Rarely present
Symptoms Symptomatic Often asymptomatic
Ketones at diagnosis Present Absent
Need for insulin therapy Immediate Years after diagnosis
Acute complications DKA HHS
Microvascular complications at No Common
diagnosis
Macrovascular complications at or No Common
before diagnosis
Symptoms of type 1 diabetes
Symptoms of type 2 diabetes
 Screening
Type 1 Diabetes Mellitus
• Screening for type 1 DM not recommended
The prevalence of type 1 DM is low in the general population.
The acute onset of symptoms in most individuals at time of
diagnosis.
• Screening for β-cell autoantibody status in high-risk family
members may be appropriate
 Screening
Type 2 Diabetes Mellitus
• ADA recommends screening
Adults without risk factors starting at age 45 years
 Repeat every 3 years if normal
Any age in individuals who are overweight (BMI ≥25 kg/m2) and
have at least one other risk factor
 Physical inactivity,
 First-degree relative with diabetes or high-risk ethnicity/race,
 Women who have delivered a baby >4 kg or a history of GDM,
 Hypertension,
 High triglycerides,
 Low HDL,
 Women with polycystic ovary syndrome,
 A1C is 5.7% or greater, IGT, or IFG in previous testing
 Acanthosis nigricans, or
 History of cardiovascular disease
 Screening
Gestational DM
Screen at first prenatal visit for undiagnosed type 2 DM

Screen at 24–28 weeks’ gestation using a 75-g OGTT.

If a diagnosis of gestational DM is made, screen for
diabetes 6 – 12 weeks after delivery.
Continue to screen patients who have had gestational
DM every 3 years for type 2 DM for life
 DM Diagnosis
1. Type 1 and type 2 DM diagnosis
a) Glycemic values in nonpregnant patients
i. FPG: ≥126 mg/dL
 Easy and preferred method
ii. Random plasma glucose: ≥200 mg/dL
 With symptoms of hyperglycemia: polyuria, polydipsia, and unexplained
weight loss
iii. OGTT: ≥200 mg/dL
 Plasma glucose concentration obtained 2 hours after a 75-g oral glucose
ingestion
iv. A1C (glycated hemoglobin): ≥6.5%
 DM Diagnosis
b) Gestational diabetes diagnosis: Glycemic values in
pregnancy
• 75-g OGTT at 24 – 28 weeks’ gestation
1 hour after OGTT: 180 mg/dL or greater
2 hours after OGTT: 153 mg/dL or greater
 DM Diagnosis

c) Prediabetes diagnosis (high-risk population)

IFG: FPG between 100 and 125 mg/dL
IGT: 2-hour plasma glucose after OGTT (75 g) between 140 and
199 mg/dL
A1C: between 5.7% and 6.4%
 Management of DM
Goals of Diabetes Management
1. Prevent the onset of acute or chronic complications.
2. Glycemic therapy goals
 A1C less than 6.5%
 Obtain every 6 months in patients at goal A1C
and every 3 months in those over goal.
 FPG: 80–125 mg/dL.
 Postprandial glucose (1–2 hours after a meal): <200
mg/dL
3. Nonglycemic therapy goals
Blood pressure <140/90 mm Hg
 Management of Type 1 DM
Insulin agents
• Categorized on the basis of duration after injection
i. Rapid acting: Insulin aspart, lispro and glulisine
ii. Short acting: Regular human insulin
iii. Intermediate acting: Neutral protamine Hagedorn (NPH)
iv. Long acting: Insulin glargine and detemir; cannot be mixed with
other insulins
• Combination insulins (intermediate or long-acting, regular
or rapid acting): 70/30, 75/25
Characteristics of U-100 (100
units/mL) Insulins
Drug Inj. Time Peak Duration
Category Clarity Onset
Name Before Meal (hours) (hours

Aspart
15–30
Rapid acting Lispro Clear 15 minutes 1–3 2–5
minutes
Glulisine

30–60
Short acting Regular Clear minutes 30 2–3 4–6

Intermediate 1–2
acting NPH Cloudy hours N/A 4–8 10–20

2–4
6–8
hours
Detemir “Peakless 6–24
1–2
Long acting Glargine Clear N/A ” ~24
hours
Degludec “Peakless 24–42
1–2
”
hours
 Management of Type 1 DM
• Glycemic target
i. Regular and short-acting insulins: target postprandial glucose
concentrations.
ii. Intermediate and long-acting insulins: target fasting glucose
concentrations.
 Insulin therapy
• Estimate total daily insulin (TDI) requirements
Weight-based estimate if insulin naïve
• 0.3 – 0.6 unit/kg/day
1. NPH (2/3) and regular (1/3) insulin
Two-thirds of TDI given before morning meal.
• Two-thirds of this is given as NPH and one third as regular insulin.
One-third of TDI given before the evening meal
• Two-thirds of this is given as NPH and one-third as regular insulin
Advantages: Daily insulin injection frequency two or three times
daily and inexpensive
Disadvantages: Does not mimic natural insulin secretion pattern;
prone to hypoglycemic events
 Insulin therapy
2. Basal/bolus insulin therapy (physiologic insulin therapy)
Use of newer insulin analogs to better mimic natural insulin
secretion patterns
Provides day-long basal insulin to prevent ketosis and control
FPG
NPH insulin twice daily, insulin glargine once daily or
insulin detemir once or twice daily
Basal requirements are 50% of estimated TDI.
Provides bolus insulin to control postprandial hyperglycemia
Rapid-acting insulin (lispro, aspart, glulisine), regular insulin
Bolus requirements are 50% of estimated TDI split three
ways before meals
 Insulin therapy
2. Basal/bolus insulin therapy
• Advantage:
More physiologic,
Less hypoglycemia,
More flexible to patient meal times
• Disadvantage:
Cost
Increased frequency and number of daily injections (rapid-acting
and basal insulin must be injected separately)
 Insulin therapy
2. Basal/bolus insulin therapy
• Correctional insulin needs
Always a need to correct for hyperglycemic excursions, despite
optimal basal/bolus therapy
“1800 rule”: 1800/TDI = # mg/dL of glucose lowering per 1 unit
of rapid-acting insulin.
For example, if TDI is 60 units, 1800/60 = 30,
suggesting 1 unit of rapid-acting insulin will reduce
BG concentrations by 30 mg/dL.
Also referred to as insulin sensitivity
 Insulin therapy
3. Continuous subcutaneous insulin infusion (CSII)
 Insulin pump
 Device allows every patient-specific hourly basal dosing and
bolus insulin dosing.
 Uses rapid-acting insulins
 Requires patient education and carbohydrate counting
Insulin Injection Sites
• Insulin absorption is affected by
1) Site: abdomen > arm, buttock
2) Exercise: increases absorption
 Case Study, Type 1 DM
• A.H., a slender, 18-year-old woman who was
recently discharged from the hospital for severe
dehydration and mild ketoacidosis, is referred to the
Diabetes Clinic. A fasting and a random plasma glucose
ordered subsequently were 190 mg/dL and 250 mg/dL.
Approximately 4 weeks before she was hospitalized, A.H.
had moved from her hometown to Addis Ababa to attend
college. This is her first time to move away from home.
 Case Study, Type 1 DM
• In retrospect, she remembers that she had symptoms
of polydipsia, nocturia (six times a night), fatigue, and a 5-
KG weight loss during this period, which she attributed to
the anxiety associated with her move away from home
and adjustment to her new environment. Her medical
history is remarkable for recurrent upper respiratory
infections and three cases of vaginal candidiasis in the
past 6 months. Her family history is negative for diabetes,
and she takes no medications.
 Case Study, Type 1 DM
• Physical examination is within normal limits. She weighs
50 kg and is 165cm tall. Laboratory results are as follows:
FPG, 280 mg/dL; A1C, 14%; and trace urine ketones. On
the basis of her history and laboratory findings, the
presumptive diagnosis is type 1 diabetes.
 Case Study, Type 1 DM
1. Which findings are consistent with this diagnosis in A.H.?
2. How do you consider insulin therapy for this patient?
 Management of Type 2 DM
Metformin
Sulfonylureas
Meglitinides
Thiazolidinediones (TZDs)
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Sodium glucose cotransporter-2 (SGLT-2) inhibitors
GLP-1 agonists
Basal insulin
 Metformin (Biguanide)
• Mechanism
Reduces hepatic gluconeogenesis.
Also favorably affects insulin sensitivity and, to a lesser extent,
intestinal absorption of glucose
• Dosing
Initial: 500 mg once or twice daily (once daily with extended-
release formulation)
Maximal daily dose: 2550 mg (more commonly, 2000 mg/day)
Can increase at weekly intervals as necessary
 Metformin
• Adverse effects
Common: Nausea, vomiting, diarrhea, epigastric pain
Less common: Decrease in vitamin B levels, lactic acidosis (rare)
 Signs or symptoms of lactic acidosis: acidosis, nausea, vomiting,
increased RR, abdominal pain, shock, and tachycardia.
• Contraindications and precautions (because of risk of
lactic acidosis)
Renal impairment
Age 80 years or older
High risk of cardiovascular event or hypoxic state
Hepatic impairment
Congestive heart failure
 Metformin
• Efficacy
1%–2% A1C reduction
Some benefit in TG reduction and weight loss
Considered first-line therapy
 Sulfonylureas
• Bind to receptors on pancreatic ß cells, leading to
membrane depolarization, with subsequent stimulation of
insulin secretion (insulin secretagogue)
• 1st – generation agents seldom used today (chlorpropamide,
tolbutamide)
• 2nd – generation agents (e.g., glyburide, glipizide,
glimepiride).
• Dosage titration: Can increase at weekly intervals as
necessary
 Sulfonylureas
• Adverse effects
Common: Hypoglycemia, weight gain
Less common: Rash, headache, nausea, vomiting,
photosensitivity
• Contraindications and precautions
Hypersensitivity to sulfonamides
Patients with hypoglycemic unawareness
Poor renal function (glipizide may be a better option than
glyburide or glimepiride)
• Efficacy
1 – 2% A1C reduction
Second-Generation Sulfonylurea
Dosing
Maximal Daily
Drug Initial Dosage Dosage (mg)
Glyburide
(nonmicronized) 2.5 – 5.0 mg once or twice daily 20
Glyburide
(micronized) 1.5 – 3 mg once or twice daily 12
5 mg once or twice daily 40
Glipizide (once daily with extended release)
Glimepiride 1–2 mg once daily 8
 Meglitinides
• Very similar mechanism to that of sulfonylureas in increasing
insulin secretion from the pancreas
• Dosing
Repaglinide
• Initial: 0.5 – 1 mg 15 minutes before meals
• Maximal daily dosage: 16 mg
Nateglinide
• 120 mg before meals
• 60 mg if A1C near goal
• Adverse effects: Hypoglycemia
 TZDs (Glitazones)
• Increases expression of genes responsible for glucose
metabolism, resulting in improved insulin sensitivity
• Dosing
Pioglitazone
• Initial: 15 mg once daily
• Maximal daily dosage: 45 mg
Rosiglitazone
• Initial: 4 mg daily as a single daily dose or in divided
doses twice daily, increase to 8 mg
 TZDs (Glitazones)
• Adverse effects
Weight gain
Fluid retention
Risk of proximal bone fractures;
Possible risk of bladder cancer (pioglitazone)
Increased risk of heart failure
• Contraindications and precautions
Hepatic impairment
Class III/IV heart failure (symptomatic heart failure)
Existing fluid retention
 DPP-4 inhibitors
• Inhibit the breakdown of GLP-1 secreted during meals,
Increase pancreatic insulin secretion,
Limits glucagon secretion,
Slows gastric emptying, and
Promotes satiety
 DPP-4 inhibitors
• Dosing
Sitagliptin: 100 mg once daily
CrCl 30 – 50 mL/min: 50 mg once daily.
CrCl < 30 mL/min: 25 mg once daily.
Saxagliptin: 5 mg once daily.
CrCl ≤ 50 mL/min: 2.5 mg once daily.
When coadministered with strong CYP3A4/5 inhibitor (e.g., ketoconazole):
2.5 mg once daily.
Linagliptin: 5 mg once daily (no dosage adjustment for renal
impairment)
Alogliptin: 25 mg once daily
CrCl 30 – 60 mL/min: 12.5 mg once daily.
CrCl <30 mL/min: 6.25 mg once daily.
 DPP-4 inhibitors
Vildagliptin : 50 mg twice daily
 CrCl <15mL/min: 50 mg once daily.

• Adverse effects
Upper respiratory and urinary tract infections, headache, severe
joint pain

• Efficacy: 0.5%–0.8% reduction in A1C,

Considered weight neutral
 SGLT-2 Inhibitor (Gliflozins)
• Increases urinary glucose excretion by blocking normal
reabsorption in the proximal convoluted tubule.
• Has some effect on delaying GI glucose absorption
Canagliflozin
• 100 mg once daily before the first meal of the day
• Maximal daily dosage: 300 mg
• CrCl 45 - 59 mL/min: 100 mg daily.
• Discontinue or do not initiate if eGFR is <45mL/min/1.73m2
 SGLT-2 Inhibitor (Gliflozins)
Dapagliflozin
• 5 mg once daily in the morning (with or without food)
• Maximal daily dosage: 10 mg
• Discontinue or do not initiate if eGFR is <60mL/min/1.73m2
Empagliflozin
• 10 mg once daily in the morning (with or without food)
• Maximal daily dosage: 25 mg
• Discontinue or do not initiate if eGFR is <60mL/min/1.73m2
 SGLT-2 Inhibitor (Gliflozins)
• Adverse effects
Increased urination
Urinary tract infections
Genital mycotic infections
Hypotension
Increased hypoglycemia risk with concomitant insulin or insulin
secretagogue
• Contraindications and precautions
Significant renal impairment
Suggested to ensure euvolemia before initiating agent
 GLP-1 analogs
• Synthetic analog of human GLP-1 that binds to GLP-1
receptors, resulting in:
Glucose-dependent insulin secretion,
Reduction in glucagon secretion, and
Reduced gastric emptying;
Promotes satiety
 GLP-1 analogs
• Exenatide:
Twice-daily formulation (5 mcg SC twice daily)
Once-weekly formulation (2 mg SC once weekly)
• Liraglutide:
0.6 to 1.2 mg SC once daily
• Albiglutide:
30 mg SC once weekly
• Dulaglutide
 0.75 mg SC once weekly
 α-Glucosidase inhibitors
• Slow the absorption of glucose from the intestine to the
bloodstream by slowing the breakdown of large
carbohydrates into smaller absorbable sugars
• Two agents available: Acarbose and miglitol
• Dosing (both agents dosed similarly)
Initial: 25 mg three times daily at each meal
Maximal daily dosage: 300 mg
• Adverse effects
Flatulence, diarrhea, abdominal pain
Increased liver enzymes observed with high dosages of acarbose
 Insulin
• Initial insulin therapy:
 Use insulin early with any of the following baseline
characteristics:
A1C greater than 10%
Glucose greater than 300 – 350 mg/dL
Hyperglycemic symptoms
Presence of urine ketones
 Insulin
• Adding insulin to existing oral DM agents
Common to add a basal insulin regimen to existing oral agents when
hyperglycemia still not controlled
Weight-based dosing: For example, 0.1–0.2 unit/kg/day
(higher dosages if significant hyperglycemia exists)
Can add bolus insulin to one or more meals if postprandial glucose is
of concern
Insulin secretagogues should be lowered in dosage or d/c altogether
when bolus insulin added to reduce risk of hypoglycemia.
TZDs should be lowered or discontinued when basal or bolus insulin
is added to regimen because of increased risk of edema
 Insulin
• Changing from oral DM medications to insulin-only
management
Because of adverse effects, contraindications, lack of efficacy of
oral medications
Can follow NPH/regular insulin or basal/bolus approach similar
to that in type 1 DM
The TDI requirements in type 2 DM are usually much higher than
in type 1 DM because of insulin resistance.
Antihyperglycemic Therapy
Recommendations in Type 2 DM
 COMPARISON OF ANTIDIABETIC AGENTS
Class Relative Hypoglycemia Weight Effect in Cardiovascular
A1C Lowering Outcome Trial

-glucosidase inhibitor  Rare Neutral to 

(acarbose)

DPP-4 Inhibitors  Rare Neutral to  alo, saxa, sita: Neutral

GLP-1R agonists  to  Rare  lira: Superiority in T2DM

patients with clinical CVD
lixi: Neutral

Insulin  Yes  Neutral (glar)

Insulin secretagogue:
Meglitinide  Yes 

Sulfonylurea  Yes 

SGLT2 inhibitors  to  Rare  empa: Superiority in T2DM

patients with clinical CVD

Thiazolidinediones  Rare  Neutral

 Antihyperglycemic agents and Renal
CKD Stage: 5 Function
4 3 2 1
eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90
a-glucosidase
Inhibitor Acarbose Not recommended 25
Biguanide Metformin 30 60
Alogliptin Not recommended
6.25 mg 30 12.5 mg 50
DPP-4
Linagliptin 15
inhibitors Saxagliptin 15 2.5 mg 50
Sitagliptin 25 mg 30 50 mg 50
Albiglutide 50
GLP-1 Dulaglutide 50
agonists
Exenatide 30 50
Liraglutide 30 50
Glimepiride 15 30
Insulin Glyburide 30 50
Secretagogues
Repaglinide
Canagliflozin 25 45 100 mg 60*
SGLT2 Dapagliflozin 60
inhibitors
Empagliflozin 45 60*
Thiazolidinediones 30
Contraindicated Not recommended Caution and/or reduce dose Safe
* = do not initiate if eGFR <60 ml/min
No dose adjustment but close monitoring of renal function
 Case Study, Type 2 DM
• L.H. is a 45-year-old, overweight woman with central obesity (height,
163cm; weight, 75 KG; BMI, 28.2 kg/m2).
• She was referred to the diabetes clinic when her gynecologist, who
had been treating her for recurrent candiadial infections, noted
glucosuria on routine urinalysis.
• Subsequently, on two separate occasions she was found to have an
FPG of 150 mg/dL and 167 mg/dL; an A1C was also checked and it
was 8.2%.
• L.H. denies any symptoms of polyphagia or polyuria, although lately
she has been more thirsty than usual.
• She does complain of lethargy and takes afternoon naps when she
can.
 Case Study, Type 2 DM
• L.H.’s other medical problems include hypertension, which is
well controlled on lisinopril 20 mg/day, and recurrent
candidial infections, which are treated with fluconazole.
• She has given birth to four children (birth weights, 3.2, 3.9,
4.5, and 5 Kg) and was told during her last pregnancy that
she had “borderline diabetes.”
• She currently works as a loan officer in a local bank and
spends her weekends “catching up on her sleep” and
reading.
• L.H. has been smoking one pack of cigarettes per day for 20
years and drinks an occasional glass of wine. She drinks at
least two regular sodas daily and has a “large” glass of
orange juice every morning.
 Case Study, Type 2 DM
• Her physical activity consists of routine walking during the
day (e.g., to her car).
• Her family history is significant for a sister, aunt, and
grandmother with type 2 diabetes; all have “weight
problems.” L.H.’s mother is alive and well at age 77; her
father died of a heart attack at age 47.
• Fasting laboratory assessment reveals glucose of 147
mg/dL, triglycerides of 400 mg/dL, and an A1C of 8.3%
(normal, 4%–6%). All other values (including the complete
blood count, electrolytes, LFTs, and renal function tests) are
within normal limits.
• L.H. is given the diagnosis of type 2 diabetes.
 Case Study, Type 2 DM

1. What features in L.H.’s history and physical examination

are consistent with this diagnosis?
2. What should the goals of therapy be for L.H. and other
patients with type 2 diabetes? Which biochemical
indices should be monitored?
3. How should L.H. be managed initially?
GDM and Pregnancy with
Preexisting DM
• The adverse outcomes associated with GDM include
Birth defects,
Miscarriage,
Cesarean section delivery,
Maternal preeclampsia/eclampsia,
Preterm delivery,
Neonatal hypoglycemia,
Shoulder dystocia,
Birth injury, and
Hyperbilirubinemia
 GDM
• Goals during therapy are
Preprandial ≤95 mg/dL
1-hour postprandial ≤140 mg/dL
2-hour postprandial ≤120 mg/dL
 GDM
• Insulin is the preferred agent for management of
pregestational type 1 DM and type 2 DM that are not
adequately controlled with diet, exercise, and metformin.
• Insulin therapy in the form of multiple injections should
be used
• For women who are non-adherent to or who refuse
insulin, glyburide or metformin may be used as
alternative agents for glycemic control
MANAGEMENT OF DM
COMPLICATIONS
• Acute complications
Hypoglycemia
Diabetic ketoacidosis
HHS
• Chronic complications
Microvascular complications
Macrovascular complications
 Hypoglycemia
• Symptoms: anxiousness, sweating, nausea, tachycardia,
hunger, clammy skin,
• Blood glucose concentration <60 mg/dL: Patient may or
may not be symptomatic.
• Blood glucose <40 mg/dL: Patient is generally
symptomatic.
• Blood glucose <20 mg/dL: Can be associated with seizures
and coma.
Hypoglycemia
SYMPTOMS

Trembling Difficulty concentrating

Palpitations Confusion
Sweating Weakness
Anxiety Drowsiness
Hunger Vision changes
Nausea Difficulty speaking
Dizziness
 Hypoglycemia
• Causes
Irregular eating patterns
↑ Physical exercise
Gastroparesis (delayed gastric emptying)
Defective counter-regulatory responses
Excessive dose of insulin or insulin secretagogues (sulfonylureas,
glinides)
Alcohol ingestion
Drugs
 Hypoglycemia
Management
• Mild to moderate hypoglycemia
Oral ingestion of 15 g glucose
• Severe hypoglycemia in a conscious person
Oral ingestion of 20 g of glucose
• Severe hypoglycemia in an unconscious individual:
No IV access:
1 mg of glucagon SC/IM
IV access
10-25 g glucose (20-50 cc of D50W) over 1-3 minutes
 Hypoglycemia
Simple Carbohydrate to treat hypoglycemia

• 15 g of glucose in the form of glucose tablets

• 15 mL (3 teaspoons) or 3 packets of sugar

dissolved in water

• 175 mL (3/4 cup) of juice or regular soft drink

• 15 mL (1 tablespoon) of honey
 Diabetic ketoacidosis
• Diabetic ketoacidosis is a reversible but potentially life-
threatening medical emergency that results from a
relative or absolute deficiency in insulin
• Without insulin, the body cannot use glucose as an energy
source and must obtain energy via lipolysis.
• This process produces ketones and leads to acidosis.
• DKA occurs frequently in young patients with T1DM on
initial presentation
 Diabetic Ketoacidosis
Clinical Presentation
• Polyuria, polydipsia, • Dehydration (tachycardia, poor
skin turgor, dry mucous
polyphagia
membranes, and orthostatic
• Weight loss hypotension)
• Fatigue • Metabolic acidosis
(compensatory deep (Kussmaul)
• Dyspnea respirations),
• Vomiting • Fruity smell on the patient's
breath.
• Preceding febrile illness
• Mental status change
• Abdominal pain (somnolence, lethargy and
coma)
 Precipitating Factors for DKA
Insulin omission – most common cause of DKA
New diagnosis of diabetes
Infection/sepsis
Myocardial infarction
Thyrotoxicosis
Drugs
 Diagnostic Criteria for DKA:
• pH ≤7.3
• Bicarbonate ≤15 mmol/L
• Anion gap >12 mEq/L
= (sodium + potassium) – (chloride + bicarbonate)
• Positive serum or urine ketones
• Plasma glucose ≥250 mg/dL (but may be lower)
• Precipitating factor
 Treatment of DKA
• Treatment
a) Fluid resuscitation
b) Avoidance of hypokalemia
c) Insulin administration
d) Avoidance of rapidly falling serum osmolality
e) Identify and treat precipitating cause
 Treatment of DKA
• Fluid replacement
The fluid deficit is typically about 100 ml/kg body weight, which
amounts to 5 – 7 L in adult patient
IV 0.9% sodium chloride 1 to 1.5 L of fluid within the first hour
and thereafter 250 to 500 ml/hour.
Change to 5% dextrose with NS when serum glucose is less
than 200 mg/dL
 Treatment of DKA
• Potassium: Correct K+ first THEN start insulin
 Treatment of DKA
• Insulin
First line:
• Intravenous bolus: 0.1 unit/kg
• Intravenous infusion: 0.1unit/kg/hour
Alternatively,
• IV infusion of 0.14 unit/kg/hour if no insulin bolus is given
Reduce infusion rate to 0.02–0.05 unit/kg/hour when serum
glucose reaches 200 mg/dL
Keep glucose between 150 and 200 mg/dL until DKA resolves
 Hyperosmolar Hyperglycemic State

• HHS occurs primarily in older patients with T2DM.

• Dx criteria: plasma glucose value of > 600 mg/dL and
serum osmolality of > 320 mOsm/kg
• Treatment:
Aggressive rehydration,
Correction of electrolyte imbalances, and
Continuous insulin infusion to normalize serum glucose.
DKA vs HHS

DKA HHS
• Ketoacidosis • Minimal acid-base problem
• ECFV contraction • ECFV contraction
• Milder hyperosmolarity • Hyperosmolarity
• Normal to high glucose • Marked hyperglycemia
• May haveLOC • Marked LOC
• Beware hypokalemia • Beware hypokalemia
• Must use insulin • May need insulin
• Absolute insulin deficiency • Relative insulin deficiency
ECFV+= extracellular
glucagon fluid volume; LOC = level of consciousness
 Treatment of Long-Term Complications

• Retinopathy
Diabetic retinopathy occurs when the microvasculature that
supplies blood to the retina becomes damaged.
Leading cause of blindness in adults
Routine ophthalmic examination
Glucose and blood pressure control
 Chronic Complications
Neuropathy
• The most common types of peripheral neuropathy are
1. Chronic sensorimotor distal peripheral neuropathy
• Pain, tingling, and numbness in the feet and hands,
2. Autonomic neuropathy
• Hypotension, gastroparesis, sexual dysfunction, and
autonomic failure in response to hypoglycemia
• Treatment:
TCAs: amitriptyline, desipramine
Anticonvulsants: gabapentin, lamotrigine, pregabalin
SSRI: paroxetine, citalopram
Opioids: tramadol
 Chronic Complications
• Nephropathy
DM is a leading contributor to end-stage renal disease.
Urine protein tests annually in T2DM patients.
Glycemic control and blood pressure control are primary
measures
ACE inhibitors and angiotensin II receptor blockers
 Chronic Complications
• Foot Ulcers
Peripheral arterial disease causes ischemia to the lower limbs.
This decreased blood flow deprives the tissues of oxygen and
nutrients and impairs the ability of the immune system to function
adequately
Loss of sensation in the feet due to neuropathies allows trauma to
go unnoticed.
Daily visual examination of the feet
Pathogenesis
 Diabetic Foot Ulcer
Patient Counselling:
1. Avoid activities that can injure the feet
2. Use care when trimming the nails
3. Wash and check the feet daily
4. Choose socks and shoes carefully
5. Routine foot exams