DIABETES

Ojomah Emono, MS 3
Robert Westbrook, MS 3
Luan Elezi, MS3
 W ha t is D ia b e t e s M e llit u s
 Defined as a group of metabolic
disorders which have a common
pathogenic process leading to
hyperglycemia
 Classified as:
 Type 1- Insulin deficiency
 Type 2- Defect in insulin action or secretion
 Preceded by impaired glucose tolerance,
and impaired fasting glucose
 Kjkd;d
 Jdlsjd;l

 Causes of Diabetes
 Type 1- β cell destruction
 Immune mediated
 Idiopathic
 Type 2- Predominant insulin resistance
 Mutations causing a defect in β cell
function
 Genetic defects of in insulin action
 Endocrinopathies



 Causes cont…
 Disease of the Pancreas
 Drug induced
 Infections
 Genetic Syndromes
 Uncommon type of diabetes
 Anti- Insulin antibodies
 Stiff Person Syndrome
 Other Etiologies of DM
 Maturity onset of diabetes of the young
(MODY)
 Autosomal Dominant Inheritance
 Early onset (less than 25 years old)
 Insulin secretion impaired
 Gestational Diabetes
 Glucose intolerance in pregnancy
 Caused by metabolic changes that occur late in
pregnancy , resulting in an increased insulin
requirement
 Occurs in 4% of pregnancies in the US
 Women usually revert back to normal glucose
tolerance after pregnancy
 Have a 30-60% risk of developing DM in the
future

 Epidemiology
 An estimated 30 million people in 1985
increased to 177 million people in 2000
 Prevalence of Type 2 increasing rapidly due
to increasing levels of obesity and
inactivity
 6 of 10 countries with the highest rates are
in Asia
 Scandinavia has the highest incidence of
Type 1 DM
 Due to the frequency of high risk HLA alleles
 Type 2 DM highest in Pacific Islands
 Due to genetic, environmental and behavioral
factors
 Highest Prevalence in the United States in
2005:
 Native Americans→ African Americans →
Hispanics → non hispanic whites
 Criteria for Diagnosis
 Symptoms of DM and random blood
glucose of 200 mg/dl
 Fasting Plasma Glucose:
 100 mg/dl- normal
 100-125 mg/dl- impaired fasting glucose
 125 and above- diabetes
 Oral glucose tolerance test
 140-199- impaired glucose tolerance
 200 diabetes 2 hours after 75 g oral
glucose load



 Screening
 American Diabetes Association recommends
individuals older than 45 be screened for
diabetes. If the person is obese the
screening should be done earlier
 Reasons for screening:
 50% of people with Type 2 have diabetes
induced complications at time of diagnosis
 Increasing number of people are unaware of
their diagnosis
 Actually have the disease 10 years before
diagnosis
 Treatment alters course of DM
 Risk Factors
 Obesity
 Family history of diabetes
 Physical inactivity
 Race/Ethnicity
 History of gestational diabetes
 History of impaired glucose tolerance or
impaired functional glucose
 Hypertension
 HDL <35 mg/dl
 Polycystic ovary syndrome
 History of vascular disease
 Acanthosis Nigricans

 Insulin Secretion
 Insulin secretion stimulated by glucose of
70 mg/dl
 Metabolism of glucose via
glycolysisinhibits the activity of ATP
dependent potassium channels .
 Binding site for oral hypoglycemic
medication
 Inward Potassium channel
 Results in βcell depolarization and
opening of voltage gated calcium
channels, causing the release of insulin.
 Insulin secreted in a pulsatile manner
( every 10 minutes)

 Action of Insulin
 Insulin induces:
 Glycogen synthesis
 Protein synthesis
 Lipogenesis
 Gene regulation in cells that are insulin
responsive
 Storage of amino acid and free fatty acids
 Storage of carbohydrates and fat

 Pathophysiology of Type 1
 Pancreatic islets are infiltrated with lymphocytes
 Antibodies to islet cells
 T lymphocytes
 Activated lymphocytes within peri-pancreatic lymph
nodes, islets and systemic circulation
 Cytokines
 Βcell death mechanisms are assumed to include
apoptosis, CD8 T cell toxicity and nitric oxide
metabolite formation
 Once the β cells are destroyed the inflammatory
process subsides and the islets become
atrophic
 Molecules targeted by the lymphocytes include:
 Insulin
 Phogrin
 Glutamic Acid Decarboxylase

Pathophysiology of Type 2
 Is a result of impaired insulin secretion,
insulin resistance, increased glucose
production or intake and atypical fat
metabolism
 In the beginning glucose tolerance
remains close to normal because the β
cells increase insulin output
 Resulting in hyperinsulinemia which
cannot be sustained. This causes
diabetes with fasting hyperglycemia.
 J;dlk;

Acute complications of Type 2
DM
 Hyperglycemic Hyperosmolar State
( HHS)
 This occurs in elderly individuals with
type 2 DM who have polyuria, or
insufficient fluid intake.
 It could also precipitated by an illness like
MI or stroke.
 HHS is manifested by marked fatigue but
it may also lead to confusion or coma in
severe cases.

Hyperglycemic Hyperosmolar
State (HHS)
 High glucose (concentration is high due to
low fluid) in the blood can cause
osmotic diuresis that results in
intravascular volume depletion making
the situation worse.
 Lab abnormalities:
 plasma glucose is 600-1200mg/d and the
osmolality being greater than
350mosmol/L.
 There is no acidosis or ketonemia in
contrast to Diabetic Ketoacidosis
 Management of HHS
 Confirm diagnosis (plasma glucose, positive serum
ketones, metabolic acidosis).
 Admit to hospital; intensive-care setting may be
necessary for frequent monitoring or if pH < 7.00
or unconscious.
 Assess:
 Serum electrolytes (K+, Na+, Mg2+ , Cl-, bicarbonate,
phosphate)
 Acid-base status—pH, HCO3-, PCO 2 , b-
hydroxybutyrate
 Renal function (creatinine, urine output)
 Replace fluids: 2–3 L of 0.9% saline over first 1–3 h
(10–15 mL/kg per hour); subsequently, 0.45%
saline at 150–300 mL/h; change to 5% glucose
and 0.45% saline at 100–200 mL/h when plasma
glucose reaches 250 mg/dL (14 mmol/L).

 Management of HHS
 Administer short-acting insulin: IV (0.1 units/kg) or IM (0.3 units/kg), then
0.1 units/kg per hour by continuous IV infusion; increase 2- to 3-fold if
no response by 2–4 h. If initial serum potassium is < 3.3 mmol/L (3.3
meq/L), do not administer insulin until the potassium is corrected to >
3.3 mmol/L (3.3.meq/L).
 Assess patient: What precipitated the episode (noncompliance, infection,
trauma, infarction, cocaine)? Initiate appropriate workup for
precipitating event (cultures, CXR, ECG).
 Measure capillary glucose every 1–2 h; measure electrolytes (especially
K+, bicarbonate, phosphate) and anion gap every 4 h for first 24 h.
 Monitor blood pressure, pulse, respirations, mental status, fluid intake
and output every 1–4 h.
 Replace K+: 10 meq/h when plasma K+ < 5.5 meq/L, ECG normal, urine
flow and normal creatinine documented; administer 40–80 meq/h
when plasma K+ < 3.5 meq/L or if bicarbonate is given.
 Continue above until patient is stable, glucose goal is 150–250 mg/dL,
and acidosis is resolved. Insulin infusion may be decreased to 0.05–
0.1 units/kg per hour.
 Administer intermediate or long-acting insulin as soon as patient is
eating. Allow for overlap in insulin infusion and subcutaneous insulin
injection.

Chronic complications of Type
2 Diabetes
 Diabetic retinopathy
 Diabetic nephropathy
 Diabetic neuropathy



Ophthalmologic complications
of DM
 Leading cause of blindness between 20 to
74 years of age in the U.S.
 People with DM are 25 times more likely
to become legally blind.
 The development of retinopathy depends
on the degree of glycemic control and
the duration of DM.
 Blindness results from progressive
diabetic retinopathy and macular
edema.
 Two stages of diabetic retinopathy
 nonproliferative and proliferative
 Nonproliferative diabetic
retinopathy
 It occurs late in first decade or early
second decade of the disease. (ten
years after the onset of first signs of
diabetes)
 It is associated with retinal vascular
microaneurysms, blot hemorrhages and
cotton wool spots.
 Pathophysiology
 There is loss of retinal pericytes, increase in
retinal vascular permeability, change in
retinal blood flow and abnormal retinal
microvasculature
 Proliferative diabetic
retinopathy
 The hallmark appearance is
neovascularization, which occur at
optic nerve and at macula.
 The new blood vessels can easily rupture
causing vitreous hemorrhage, fibrosis
and retinal detachment
 Renal complications of
Diabetes Mellitus
 Diabetic nephropathy is the cause of
ESRD.
 The pathogenesis of diabetic nephropathy
is related to chronic hyperglycemia.
 Mechanism of chronic hyperglycemia
progressing to ESRD
 involve effects of soluble factors such as
growth factors, angiotensin II and
endothelin
 Alteration in renal microcirculation like
glomerular hyperfiltration and rise in
glomerular capillary pressure.
 And structural changes in glomeruli for
example BM thickening, mesangial
expansion, high extracelluar matrix
 Renal complications
continued
 The first 5 years of diabetes it involves
glomerular BM thickening and
mesangial volume expansion.
 In 5 to 10 years of type 1 DM, individuals
excrete small amounts of albumin in
urine.
 Microalbuminuria is 30-300mg/d
 Macroabluminuria occurs over the next 10
years
 Diabetic Neuropathy
 The occurrence of diabetic neuropathy is
determined by the duration of diabetes
and the glycemic control.
 This has two types
 symmetric and asymmetric types

 Neuropathies
 Symmetric neuropathy can present as
small fiber involvement (e.g.
dysesthesias in the feet) or autonomic
dysfunction ( e.g. sexual impotence)
 Asymmetric neuropathy categorized into
acute and gradual onset.
 Examples of acute onset:
 diabetic truncal radiculoneuropathy (DTRN),
diabetic lumbosacral radiculoplexus
neuropathy (DLSRPN) and oculomotor
neuropathy
 Neuropathies
 Diabetic neuropathies of gradual onset
are by entrapment/compression of
median at wrist, ulnar at elbow,
peroneal at fibular head and lateral
cutaneous at the inguinal ligament.

 Type 2 DM Therapy
 Control through Diet and Weight Loss
 Use of Oral Hypoglycemic Agents
 Sulfonylureas
 Meglitinides
 Biguanides
 Thiazolidinediones
 Alpha-Glucosidase Inhibitors

 SULFONYLUREAS
 Increases Beta cell production of insulin
 First Generation Drugs:
 Tolbutamide, Chlorpropamide
 Second Generation Drugs:
 Glyburide, Glipizide, Glimepiride
 Side Effect: for examples
 Tolbutamide: Tinnitus
 Chlorpropamide: hypoglycemia, Disulfiram-
like rxn

 MEGLITINIDES
 Increase Beta Cell production of insulin
 Drug Name: Repaglinide
 Usage: a fast acting premeal therapy to
limit postprandial hyperglycemia
 Side Effect: can cause hypoglycemia
when taking together with gemfibrozil

 BIGUANIDES
 Increases peripheral cell sensitivity to
insulin
 Drug Names: Metformin, Phenformin
 Avoid the use of this drug in renal
impairment or prior to radiologic dye
procedure for potential acute renal
failure
 Adverse Effect: Lactic acidosis, diarrhea
 THIAZOLIDINEDIONES
 Increases tissue sensitivity of peripheral
cells and hepatic cell to insulin
 Drug Names: Rosiglitazone, Pioglitazone
 Metabolized by cytochrome P450 system
 Contraindication:
 Severe heart failure, liver disease
 Adverse Effect: hepatotoxicity
 Alpha-Glucosidase
Inhibitors
 Decrease absorption of disaccharides by
inhibiting alpha-glucosidase
 Drug Names: Acarbose, Miglitol
 Have minimal effects on blood sugar--
they do not stimulate insulin release
 Metabolized within the GI tract by flora
 Adverse effects: Flatulence, diarrhea
