1. DIABETES MELLITUS

2. DEFINITION
• A metabolic syndrome characterized by
hyperglycemia
• ADA definition of DM:
1. FPG(FBS) ≥126 mg/dl,
2. NPG(RBS) ≥200 mg/dl, or
3. OGTT ≥200 mg/dl in the 2-hr sample
• Upper limit of normal FBS=100 mg/dl
• FBS= 100 to 126 mg/dl  IFG
• OGTT=110 mg/dl and 200 mg/dl IFG

3. Type 1 Type 2
Age of
Onset
Usually <30 yr,
particularly childhood
and adolescence, but any
age
Usually >40 yr,
but any age
Genetic
predisposition
Moderate;
environmental
factors required for
expression: 35%-50%
concordance in
monozygotic twins;
several candidate
genes proposed
Strong; 60%-90%
concordance in
monozygotic twins;
many candidate
genes proposed;
some genes
identified in MODY
HLA
Associations
Linkage to DQA and
DQB, influenced by
DRB (3 and 4) (DR2
protective)
None
known

4. Type 1 Type 2
Other
Associations
Autoimmune; Graves'
disease, Hashimoto's
thyroiditis, vitiligo,
Addison's disease,
pernicious anemia
Heterogenous group,
ongoing subclassification
based on identification of
specific pathogenic
processes and genetic
defects
Precipitating and
Risk Factors
Largely unknown;
microbial, chemical,
dietary, other
Age, obesity (central),
sedentary lifestyle,
previous gestational
diabetes
Findings at
diagnosis
85%-90% of patients
have one and usually
more autoantibodies
to ICA512/IA-2/IA-2β,
GAD65, insulin (IAA)
Possibly complications
(microvascular and
macrovascular)
caused by significant
preceding
asymptomatic period

5. Type 1 Type 2
Endogenous
Insulin Levels Low or absent
Usually present
(relative deficiency),
early
hyperinsulinemia
Insulin
Resistance
Only with
hyperglycemia
Mostly present
Prolonged Fast Hyperglycemia, DKA Euglycemia
Stress, withdrawal
of insulin
DKA HNKS,
occasionally
DKA

6. EPIDEMIOLOGY
• Prevalence: U.S. population vs. Pima Indians
DM= 5% to 7% vs. 35%
• Incidence: 2% in 20 to 44 yr olds vs. 18% in 65
to 74 yr olds
• 8% of all legal blindness
• Leading cause of ESRD in the US
• CVS- disease: 2x the risk in non- DM patients

7. CLINICAL PRESENTATION - Hx
• Type-1-Poly symptoms ± DKA
• Type-2-Asymptomatic
• Sometimes weight loss;
occasionally poly symptoms
• Often- chronic complications
• Paresthesias (feet > hands);
• Symmetric, bilateral, intense
burning pain (more at night)

8. CLINICAL PRESENTATION- P/E
• Normal in early stages
• Diabetic retinopathy:
a. Non-proliferative (background diabetic
retinopathy):
1. Initially: micro-aneurysms, capillary
dilation, waxy or hard exudates, dot
and flame hemorrhages, AV shunts

9. CLINICAL PRESENTATION- P/E
2. Advanced stage: micro-infarcts with
cotton wool exudates, macular edema
b. Proliferative retinopathy: formation of
new vessels, vitreal hemorrhages,
fibrous scarring, and retinal
detachment
• Cataracts and glaucoma

10. CLINICAL PRESENTATION- P/E…
• Peripheral neuropathy:
a. Mononeuropathies- CN- III, IV, and VI
 Diplopia, abnormalities of visual
fields
-intercostal nerves, and femoral nerves
b. Sensation
c. Motor- DTR, weakness and atrophy of
interossei muscles

11. CLINICAL PRESENTATION- P/E…
• Autonomic neuropathy:
a. GI disturbances: esophageal motility
abnormalities, gastroparesis, diarrhea
(usually nocturnal)
b. GU disturbances: neurogenic bladder
(hesitancy, weak stream, and
dribbling), impotence

12. CLINICAL PRESENTATION- P/E…
c. Orthostatic hypotension: postural
syncope, dizziness, light-
headedness
• Nephropathy: pedal edema, pallor,
weakness, uremic appearance
• DFU: 15% of DM pts (incidence
2%/yr), leading cause of
hospitalization

13. CLINICAL PRESENTATION- P/E…
• Neuropathic arthropathy (Charcot's
joints)
• Necrobiosis lipoidica diabeticorum:
- plaque like reddened areas
- central area that fades to white-
yellow
- on anterior surfaces of the legs;
- very thin; can ulcerate readily

14. ETIOLOGY
• Type 1 DM
• Hereditary factors:
1. ICA (in 90% of pts in the 1st yr of dx)
2. Higher incidence of HLA types DR3, DR4
3. 50% concordance in identical twins
4. Environmental factors: viral infection
(possibly coxsackie virus, mumps virus)

15. ETIOLOGY…
• Type 2 DM
• Hereditary factors: 90% concordance in identical
twins
• Environmental factor: obesity
• DIABETES 2° TO OTHER FACTORS:
• Hormonal excess: Cushing's syndrome,
acromegaly, glucagonoma, pheochromocytoma
• Drugs: glucocorticoids, diuretics, oral
contraceptives

16. ETIOLOGY…
• DIABETES 2° TO OTHER FACTORS:
• Insulin receptor unavailability (with or
without circulating Ab)
• Pancreatic disease: pancreatitis,
pancreatectomy, hemochromatosis
• Genetic syndromes: hyperlipidemias,
myotonic dystrophy, lipoatrophy
• Gestational diabetes

17. The Clinical Pattern of DM in Ethiopians
Diabetes Care. 1984 Jan-Feb;7(1):6-11, Lester FT.
• Among 849 Ethiopians with DM
• 171 -type I, 462 type II nonobese, 210 type II
obese, and 4 drug-induced
• Undernutrition (BMI less than 18 kg/m2)-
12.9%
• DKA- 7.8%
• 73%- ≤10 yr of DM, 11% - ≥15 yr, and none
>32 yr

18. The Clinical Pattern of DM in
Ethiopians
• During 7 yr, 66 (7.8%) are known to have died
(CRF 30.3%, and DKA 3%)
• ~4% with 6-10 yr DM- clinically significant
complication
• “Diabetic triopathy" at 16-20 yr - 27.7% had
nephropathy, 27.7% neuropathy, and 33.3%
retinopathy
• Cataracts- 1.4% of new DM patients, 40.7% in
>20 y DM

19. DIFFERENTIAL DIAGNOSIS
• Diabetes insipidus
• Stress hyperglycemia
• Diabetes secondary to hormonal
excess, drugs, pancreatic disease

20. LABORATORY TESTS
1. Fasting glucose ≥126 mg/dl
2. Nonfasting plasma glucose ≥200 mg/dl
• DM- nephropathy- microalbuminuria -
2 to 3 elevated levels within 3- to 6-
months
• Yearly fasting serum lipid panel, serum
creatinine, and electrolytes

21. NONPHARMACOLOGIC THERAPY
• Diet - Calories
- 15 cal/lb of ideal body weight;
- 20 cal/lb for an active person and
- 25 cal/lb for heavy physical labor
- 50% to 60% carbohydrates, <30%
fat, 15% to 20% protein

22. NONPHARMACOLOGIC THERAPY…
• Glycemic index
• Fibers: delay glucose absorption and
attenuate the postprandial serum glucose
peak
• Lower the elevated triglyceride level often
present in uncontrolled diabetics(20 to 35
g/day of soluble and insoluble fiber)

23. NONPHARMACOLOGIC THERAPY…
• Sodium restriction: -2400 to 3000 mg/d
- <2400 mg/d- If hypertensive
- <2000 mg/d- nephropathy and htn
• Exercise
• Weight loss
• Screening for nephropathy, neuropathy,
and retinopathy

24. OHA’s
• OHA’s (metformin, sulfonylureas, repaglinide
& acarbose , miglitol, pioglitazone &
rosiglitazone )
• Sitagliptin- inhibits the enzyme DPP-4
(inactivates and degrades GLP-1 & GIP)
↑insulin synthesis and release and decrease
glucagon production
• ↓HbA1c of 0.5% vs. 1.5% for metformin

25. INSULIN
• Injectable/Inhaled insulin
• ~50% to 60%- long-acting insulin- 1-2x/d,
• 40% to 50%- short/rapid acting (aspart,
lispro> regular)
• Bedtime insulin glargine -↓risk of nocturnal
hypoglycemia and less weight gain
• Insulin detemir - long-acting insulin analog
• not associated with weight gain

26. THERAPY
• Pramlintide (Symlin), synthetic analog of
human amylin
• Exenatide (Byetta), synthetic peptide ,
stimulates release of insulin
• CSII, or insulin pump- DM presenting in
childhood/adolescence /pregnancy
• ASA- 81 mg/d
• Strict lipid control (LDL<70 mg/dl)

27. CHRONIC COMPLICATIONS
• Diabetic retinopathy is - ~15% at 15
yr, increases 1%/yr after diagnosis
• Neuropathy in type 2 DM- ~70% to
80%
• Nephropathy- 35% to 45% in type 1
DM and 20% in type 2 DM

28. PREVENTION
• DCCT- intensive treatment- ↓risk of
retinopathy, nephropathy, and neuropathy
by 35% to 90%
• Annual ophthalmologic examination
• Podiatric care
• HbA1C- twice yearly
• Microalbumin - yearly
• Creatinine and serum-lipid panel - yearly

29. DKA
• Severe dehydration and alterations in sensorium
resulting from severe insulin deficiency
• Mortality: ~ 2-4 % in adults; ↑as age > 50 (5% to
10%)
• ~ 0.2-0.4% in children; mostly 2⁰ to cerebral
edema
• Children <10 yr, DKA  70% of DM related
deaths
• Cerebral edema occurs in 1% of episodes of DKA
in children; mortality rate of 40% to 90%.

30. EPIDEMIOLOGY
• INCIDENCE/PREVALENCE: 46
episodes /10,000 diabetics;
cause of 14% of all hospital
admissions of diabetic patients
• PREDOMINANT AGE: 1 to 25 yr

31. ETIOLOGY-“The Four I’s”

32. Pathophysiology
Insulin Deficiency/Resistance
Counter Regulatory Hormone Excess

33. Pathophysiology...
• Insulin action in normal host
–Decrease blood glucose via decreasing
hepatic glucose production
–Decrease ketone production via
decrease in lipolysis and glucagon
secretion
–Peripheral tissue utilization of glucose

34. Pathophysiology...
• The antilipolytic action of insulin occurs
at much lower concentrations of insulin
than does it’s glucose lowering effects
–Any dose of insulin that corrects sugars
should correct ketoacid production
–No ketoacid production in Type II as these
diabetics have small amounts of
endogenous insulin

35. Pathophysiology...
• Presence of ketones GI symptoms
stop drinking and get sick faster
–1-2 days in DKA VS 1 week in HHS
• 3 Ketones
–Acetoacetate captured on urine dip and
levels increase as DKA resolves
–Beta-hydroxy-butyrate main ketone
(75%) in DKA, often not measured directly
–Acetone “fruity breath” in 5% pt’s

36. CLINICAL PRESENTATION
• Evidence of dehydration
• Clouding of mental status
• Kussmaul's respiration
• Fruity breath odor
• Lipemia retinalis in some patients
• Possible evidence of precipitating factors
• Abdominal or CVA tenderness in some
patients

37. DIFFERENTIAL DIAGNOSIS
• Hyperosmolar nonketotic state
• Alcoholic ketoacidosis
• Uremic acidosis
• Metabolic acidosis secondary to
methyl alcohol, ethylene glycol
• Salicylate poisoning

38. Feature DKA HNKS
Age of patient Usually <40 yr Usually >60 yr
Duration of symptoms Usually <2 days Usually >5 days
Serum glucose Usually <800 mg/dl Usually >800 mg/dl
Serum Na+ Likely normal or low Likely normal or high
Serum HCO3 Low Normal
Ketone bodies At least 4 + in 1:1 dilution <2 + in 1:1 dilution
pH Low Normal
Serum osmolality Usually <350 mOsm/kg Usually >350 mOsm/kg
Cerebral edema Occasionally clinical
symptoms
Rarely (never?) clinical
Prognosis 3%-10% mortality 10%-20% mortality
Subsequent course Insulin therapy required
in almost all cases
Insulin therapy not
required in most cases

39. LABORATORY TESTS
• Pco2 <40 mm Hg
• 1. Serum HCO⁻₃ <18 mEq/L.
2. Serum K⁺ may be low, normal, or high
3. Serum Na⁺ is usually decreased
(hyperglycemia, dehydration, and
lipemia)
4. Calculate AG: AG = Na+ - (Cl- + HCO-3)

40. LABORATORY TESTS…
• CBC with differential, urinalysis,
urine and blood cultures to rule out
infectious precipitating factor
• Serum Ca⁺, Mg⁺, and P0₄⁻
• BUN and creatinine
• Amylase, liver enzymes if abdominal
pain

42. OTHER INVESTIGATIONS
• ECG
• Chest x-ray- may be negative if there is
significant dehydration

43. NONPHARMACOLOGIC THERAPY
• Monitor mental status, vital signs, and urine
output qh until improved, then monitor q2 to
4h
• Monitor electrolytes, renal function, and
glucose level

44. DKA: Management Goals
• Replacement of fluid deficits
• Resolution of metabolic
ketoacidosis (pH >7.3, AG < 12, BG <12)
• Correction of electrolyte
abnormalitiesHCO3 >18
• Diagnose and treat coexisting
illnesses
• Prevent complications

45. FLUID REPLACEMENT
• “Focus on shock NOT sugar”
– Average deficit is 100ml/kg or 5-7L
– Fluid loss 2⁰ to osmotic diuresis
• Fluid resuscitation alone will lead to
improvements in acidosis and blood sugar
– ~80% reduction of BG in 1st 4 hr of therapy is
from fluids alone
• First step is to attain euvolemia

46. FLUID REPLACEMENT…
• If the patient is “shocky”- IV NS 1-2 L/hr
• Rough guide: correct ½ deficit in 1st 8-12
hrs and the remainder over 12-16hrs:
–IV NS 500 ml/hr X 4hr
–IV NS 250 ml/hr X 4hr
–Change to D5NS or D10 when BS < 14
mmol/L
• If Na is normal or elevated ½ NS

47. DKA: R. Insulin(0.1U/Kg/hr)
• Insulin is used to treat acidemia/ketonemia
– The effects on blood sugar are secondary
– Average time to clearance: 18 hours
– No rush to start insulin, no need to give large
amounts up front
– Find out serum potassium before starting
insulin
– Titrate insulin drip against the anion gap,
serum ketones

48. Serum Potassium Action
< 3.3 Hold Insulin
Give 40 mmol/L KCL if
u/o
3.3-5 Start insulin drip
KCL @ 10-40 mmol/L
>5 Start insulin drip
Hold potassium, re-
check K in 2 hr

49. HKNS
• A state of extreme
hyperglycemia, marked
dehydration, serum
hyperosmolarity, altered mental
status, and absence of
ketoacidosis

50. CLINICAL PRESENTATION
• Evidence of extreme dehydration
• Neurologic defects (reversible
hemiplegia, focal seizures)
• Evidence of precipitating factors
(pneumonia, infected skin ulcer)
• Coma (25% of patients), delirium

51. ETIOLOGY
• Infections, 20% to 25%
• New or previously unrecognized diabetes (30%
to 50%)
• Reduction or omission of diabetic medication
• Stress (MI, CVA)
• Drugs: diuretics (dehydration), phenytoin,
diazoxide (impaired insulin secretion),
glucocorticoids, chemotherapeutic agents,
calcium channel blockers, TPN, substance abuse
(alcohol, cocaine)

52. DIFFERENTIAL DIAGNOSIS
• Diabetic ketoacidosis
• Differential diagnosis of coma

53. LABORATORY TESTS
• Serum glucose usually >600 mg/dl,
serum/urine ketones absent or “small.”
• Serum osmolarity usually >320 mOsm/L
• Serum Na: may be low, normal, or high
• Serum K: may be low, normal, or high (body
deficit ~5 to 15 mEq/kg)
• Serum HCO₃: usually >15 mEq/L (average is
17 mEq/L)

54. LABORATORY TESTS…
• Arterial pH: usually >7.3
• BUN: (60 to 90 mg/dl)
• ↓PO₄⁻ (average deficit is 70 to 140 mm)
• ↓Ca (average deficit is 50 to 100 mEq)
• ↓Mg (average deficit is 50 to 100 mEq)
• CBC with differential, urinalysis, blood and
urine cultures should be performed to rule
out infectious etiology

55. OTHER INVX
•Chest x-ray
•CT scan of head -
suspected CVA

56. MANAGEMENT
• Fluid replacement: 1000 to 1500 ml/hr 0.9% NS
for the initial 1 to 2 L; then 500 ml/hr
• Serum glucose 300 mg/dl 5% DW with 0.45%
NS
• Replace electrolytes and monitor serum levels
frequently (e.g., serum Na and K q2h for 12 hr)
• Continuous ECG monitoring and urinary output
Qhr
• Severe hypoK (<3.3 mEq/L) 40 mEq of K/hr
until K is >3.3 mEq/L.

57. MANAGEMENT
• Correct glucose by at least 50 to 100
mg/dl/hr
• Vigorous IV hydration  by 80 mg/dl/hr;
• Regular insulin IV bolus (0.15 U/kg of body
weight)
• Insulin infusion- 0.1 U/kg/hr till BS ~300
mg/dl; then regular SC insulin (sliding scale)
• BS q1-2h in the initial 12 hr