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Diabetes - Complications

Diabetes Complications
Contents
1. Define the term diabetes mellitus, and indicate the common investigations
used in the diagnosis and monitoring of this condition.........................................4
Definition............................................................................................................ 4
Evaluation........................................................................................................... 4
Initial............................................................................................................... 4
Diabetic related complications........................................................................4
Gestational Diabetes Screening......................................................................5
Diagnosis............................................................................................................ 5
2. Distinguish between type1, type 2 and gestational diabetes on
epidemiological and clinical grounds.....................................................................6
3. Describe the role of insulin in carbohydrate and lipid metabolism. What broad
categories of insulins are available?......................................................................7
Glucose homeostasis.......................................................................................... 7
4. Describe the pathogenesis of the common forms of diabetes mellitus, and
outline the major risk factors for their development.............................................9
Diabetes Type 1.................................................................................................. 9
Genetic Susceptibility...................................................................................... 9
Environmental Factors..................................................................................... 9
Mechanisms of cell destruction....................................................................9
Type 2 DM......................................................................................................... 10
Insulin Resistance.......................................................................................... 10
5. Describe the biochemical basis of the major metabolic disturbances in
diabetes, including ketoacidosis and hyperglycaemic coma, and the likely
metabolic consequences of these conditions......................................................12
Diabetic Ketoacidosis........................................................................................ 12
Other Metabolic Disturbances..........................................................................13
6. Describe the macrovascular and microvascular complications of diabetes,
with emphasis on diabetic retinopathy and nephropathy. What pharmacotherapy
is indicated to slow down the progression of these complications, and why?......14
Macrovascular.................................................................................................. 14
Overall pathophysiology of complications of DM..............................................14
Diabetic Nephropathy....................................................................................... 14
Morphological Changes................................................................................. 15
Pathogenesis................................................................................................. 15

Diabetes - Complications
Diabetic Retinopathy........................................................................................ 15
Classification................................................................................................. 16
Pathophysiology............................................................................................ 16
Management................................................................................................. 16
7. Discuss the factors that may result in the development of a foot ulcer in an
individual with diabetes mellitus.........................................................................17
Diabetic Neuropathy......................................................................................... 17
Classifications................................................................................................ 17
Symptoms..................................................................................................... 17
Foot Ulcers.................................................................................................... 17
Pathophysiology of Foot Ulcers......................................................................18
Risk Classification............................................................................................. 18
Group 0......................................................................................................... 18
Group 1......................................................................................................... 18
Group 2......................................................................................................... 18
Group 3......................................................................................................... 18
8. List the microorganisms most commonly associated with foot ulcers in a
diabetic patient and outline the treatment strategy that you would recommend.
19
Microorganisms................................................................................................ 19
Antibiotics...................................................................................................... 19
9. Discuss the nature and pathogenesis of neurological lesions seen in longstanding diabetes mellitus................................................................................... 20
10. What pharmacotherapies are available for type 1 and type 2 diabetes?
Why do the treatments differ?.............................................................................21
Goals of Therapy.............................................................................................. 21
Diabetes Type 1................................................................................................ 21
Lifestyle......................................................................................................... 21
Glycaemic targets......................................................................................... 21
Insulin............................................................................................................ 21
Choice of insulin regimen..............................................................................22
Type 2 Diabetes................................................................................................ 22
Glucose Lowering Agents.............................................................................. 22
11. Explain the importance of ongoing monitoring of blood glucose levels in
diabetes............................................................................................................... 26
Glucocorticoids.................................................................................................... 27

Diabetes - Complications

1. Define the term diabetes mellitus, and indicate

the common investigations used in the diagnosis
and monitoring of this condition.
Definition

Group of metabolic disorders sharing common underlying feature of

hyperglycaemia
Hyperglycaemia results from
o Insulin secretion
o Insulin action
o Both
Morbidity is from macrovascular diseases (such as arteriosclerosis) or from
microvascular (retinopathy, nephropathy or neuropathy).

Evaluation
Initial

History and examination of to assess characteristics of onset of diabetes

o Asymptomatic laboratory findings
o Symptomatic polyuria and polydipsia
o Nutrition and weight history
o Physical activity
o Cardiovascular risk factors
o History of diabetic related complications
o Hypoglycaemic episodes
o DKA
o Current management
Glycated haemoglobin (HBA1C)
Fasting lipid profile, LFTs, urine albumin excretion (spot urine), serum
creatinine
TSH in diabetes mellitus 1

Diabetic related complications

2-3 check ups annually

o Blood pressure check
o Feet visually checked
Problems with nail care, poorly fitting footware, fungal
infections and callus formation
Inspection, assessment of foot pulses, testing for loss of
sensation
History of claudication and assessing pedal pulses
o Dilated eye exam annually
HbA1C measured every three months if not in goal range (goal range
<7%)
HbA1C measured every six months if stable
Stringent HbA1C goals (<6%) aimed for those that are DMT1 or pregnant
Fasting lipids and albumin:creatinine measured yearly

Diabetes - Complications

Gestational Diabetes Screening

All women tested at 26 weeks gestation, using Glucose Challenge test or

OGTT
o Glucose Challenge Test
Oral glucose 50g/75g in non-fasting state test 1 hour later
if blood glucose >7.8mmol/L, OGTT required
o OGTT
Oral 75g glucose in fasting state gestational diabetes if
fasting glucose >5.5mmol/L or >8mmol/L after 2 hours

Diagnosis

Blood glucose values normally 700-1200mg/L

Nondiabetic range when random/fasting glucose concentration
<5.5mmol/L
Diagnosis is through one of these:
o Random glucose concentration greater than 2g/L (11.1mmol/L) with
classical signs and symptoms
o Fasting glucose concentration greater than 1260g/L (7mmol/L) on
more than one occasion.
o Abnormal oral GTT in which glucose concentration is >2g/L 2 hours
after a standard carb load
o HbA1C > 6.5% (48mmol/mol)

Oral GTT done only if fasting/random glucose is high

Diabetes - Complications

2. Distinguish between type1, type 2 and gestational

diabetes on epidemiological and clinical grounds.

Type 1 Diabetes:
o Characterised by pancreatic cell destruction and absolute
deficiency of insulin
Type 2 diabetes
o Combination of peripheral resistance to insulin action and adequate
secretory response by pancreatic cells
o Most are overweight
o Two metabolic defects that characterise:
Decreased response of peripheral tissues to insulin
cell dysfunction that is manifested as inadequate insulin
secretion in face of insulin resistance and hyperglycaemia.

Diabetes - Complications

3. Describe the role of insulin in carbohydrate and

lipid metabolism. What broad categories of insulins
are available?

Insulin is most potent anabolic hormone known

Principle metabolic function is to increase the rate of glucose transport
into certain cells in the body, providing increased source of energy. These
include:
o Striated muscle cells (including myocardial cells)
Glucose is stored as glycogen or oxidised to generate ATP
o Adipocytes to a lesser extent
Glucose is stored as lipid
Insulin also inhibits lipid degradation in adipocytes
Insulin also promotes amino acid uptake and protein synthesis, while
inhibiting protein degradation.
Glucose uptake in other peripheral tissues such as the brain is insulin
dependent.

Anabolic effects of insulin are attributable to increased synthesis and

reduced degradation of glycogen, lipids, and proteins.

Glucose homeostasis

Normal glucose homeostasis regulated by 3 interrelated processes:

o Glucose production in liver
o Glucose uptake and utilisation by peripheral tissues (mostly skeletal
muscle)
o Actions of insulin and counter-regulatory hormones, including
glucagon produced by pancreatic cells, on glucose uptake and
metabolism
Actions of glucagon and insulin
o During fasting states, there is low insulin and high glucagon levels
Glucagon helps facilitate hepatic gluconeogenesis and
glycogenosis
At the same time, it decreases glycogen synthesis,
preventing hypoglycaemia.

Diabetes - Complications
Fasting plasma glucose levels hence depend on hepatic
glucose output
After a meal, there is high insulin and low glucagon
Insulin promotes glucose uptake and utilisation in tissues
Skeletal muscle is major insulin-responsive site for
postprandial glucose utilisation, critical for preventing
hyperglycaemia and maintaining glucose homeostasis.

Glut-2
o Insulin independent glucose transporter in cells
Glucose undergoes oxidative metabolise to produce ATP
ATP inhibits inward K+ channel receptors on cell surface
This leads to membrane depolarisation, influx of Ca 2+ ions, and release of
stored insulin from cells.
Sulphonylurea binds to SUR1 receptor protein on K + channels and causes
blockage of K+ channel for depolarisation.
Other hormones and certain amino acids such as leucine and arginine also
stimulate insulin release

Diabetes - Complications

4. Describe the pathogenesis of the common forms of

diabetes mellitus, and outline the major risk factors
for their development.
Diabetes Type 1

Islet destruction caused by immune effector cells reacting against

endogenous cell antigens
Can develop at any age

Genetic Susceptibility

HLA locus on chromosome 6p21 (contributes as much as 50% of the

genetic susceptibility to T1DM)
o Most have a HLA-DR3 or HLA-DR4 haptotype

Environmental Factors

Viral factors may be involved

Mumps, rubella, Coxsackie B or cytomegalovirus
Three mechanisms:
o Bystander damage:
Viral infections cause islet injury and inflammation, leading to
release of sequestered cell antigens and activation of
autoreactive T cells
o Molecular mimicry: Viruses produce proteins that mimic cell
antigens, and immune response to viral protein cross-reacts with selftissue
o Islet dj vu: Predisposing virus infections in tissues may experience
precipitating virus (related virus) infections, which can lead to
immune response against infected islet cells.

Mechanisms of cell destruction

Autoimmune process usually starts many years before the disease

becomes evident, with progressive loss of insulin reserves over time
Main idea: Failure of self-tolerance in T cells. T cells respond to selfantigens.
o May be due to defective clonal deletion of self-reactive T cells in the
thymus during production
o Defects in function of regulatory T cells
Initial activation of cells thought to occur in peripancreatic lymph nodes, in
response to antigens that are released from damaged islets
o Activated T cells travel to pancreas, where they cause cell injury
o T cell populations include TH1 cells(which are CD4+) (which release
cytokines such as IFN-, TNF and IL1 to activate macrophages) and
CD8+ CTLs (which directly kill cells).
Initially, in the first two years following the onset of T1DM, exogenous
insulin requirements may be minimal because of ongoing endogenous
insulin secretion.
o After, residual cell reserve is exhausted and insulin requirements
increase dramatically.
Other islet cell types ( cells glucagon, cells somatostatin) are not
autoimmunely destroyed

Diabetes - Complications

Type 2 DM

Environmental factors: sedentary life style, dietary habits

Risk is 40% if both parents affected.
Strong genetic component
Unlike T1DM, T2DM not related to genes involved in immune tolerance and
regulation (HLA, CTLA4 etc) and there is no evidence of an autoimmune
activity

Insulin Resistance

Failure of target tissues to respond normally to insulin.

Decreased uptake of glucose into muscle, decreased glycolysis, and fatty
acid oxidation in liver, inability to supress hepatic gluconeogenesis.
Loss of insulin sensitivity in hepatocytes likely to be largest contributor to
pathogenesis of insulin resistence.
Obesitys impact on insulin sensitivity:
o Nonesterified fatty acids (NEFAs): Inverse correlation between
nonesterified fatty acids and insulin sensitivity.
Released from adipocytes by action of hormone sensitive
lipase (HSL), which will hydrolyse stored triglycerides to
produce NEFA and glycerol.
NEFA bound to albumin and transported to muscle and liver
tissues (excess NEFAs are deposited here)
NEFAs produce toxic metabolites which can cause serine
phosphorylation of insulin receptors, which attenuates insulin
signalling (lipotoxicity).
Furthermore, attenuated insulin receptors can exacerbate
liver gluconeogenesis.
NEFAs also compete with glucose for oxidation, exacerbating
the glucose imbalance.
o Inflammation:
Adipose tissue secretes proinflammatory cytokines including
TNF, IL6, etc.
Reducing these cytokine levels enhances insulin sensitivity.
These cytokines induce insulin resistance by increasing
cellular stress which activates signalling cascades which can
antagonise insulin action on peripheral tissues.
o Adipocytes resulting in decreased adiponectin:
Fat is a functional endocrine organ that releases hormones in
response to changes in metabolic status.
Pro hyperglycaemic and anti-hyperglycaemic adipokines
(leptin, adiponectin) have been identified.
Adiponectin acts upon AMP-activated protein kinase AMPK
which promotes fatty acid oxidation
Adiponectin levels are reduced in obesity, contributing
to insulin resistance.
o Increased hepatic glucose and lipid production
Increased lipolysis and free fatty acid from adipocytes
released due to insulin resistance

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Diabetes - Complications

Leads to increased lipid (LDL) and triglyceride synthesis in

hepatocytes

cell failure
o cells can exhaust capacity to adapt to long term demands of
peripheral insulin resistance
i.e. over-production of insulin exhausts the cells
o Hyperinsulinaemic state is compensation for peripheral resistance
which can last for years
Eventually cell compensation becomes inadequate, and
there is progression to hyperglycaemia.
Eventual cell failure
o Excess NEFAs leading to lipotoxicity can cause this.
o Agents like metformin improve AMPK activation and improve cell
function

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Diabetes - Complications

5. Describe the biochemical basis of the major

metabolic disturbances in diabetes, including
ketoacidosis and hyperglycaemic coma, and the
likely metabolic consequences of these conditions.

Onset of DM marked by polyuria, polydipsia, polyphagia, and

ketoacidosis due to metabolic derangements
Deficiency of insulin results in catabolic state that affects not only
glucose metabolism but also fat and protein metabolism.
Unopposed secretion of counter-regulatory hormones such as
glucagon, growth hormone, and epinephrine.
Glycogen stores in liver and muscle are depleted by glycogenolysis.
Resultant hyperglycaemia exceeds renal threshold for reabsorption
(glucose maximum) and glycosuria results.
Glycosuria induces osmotic diuresis and hence polyuria.
Water loss and hyperosmolarity of glucose in blood depletes
intracellular water, triggering osmoreceptors polydipsia.

If patient does not drink enough water,

Hyperosmolar nonketotic coma (hyperglycaemic coma) may develop

Dehydrated patients have high osmolar concentrated urine due to
glucose. Results in polyuria.
Typically, patient is elderly diabetic who is disabled by stroke or
infection and unable to maintain adequate water intake.
Absence of ketoacidosis and its symptoms (nausea, vomiting,
respiratory difficulties) delays seeking of medical attention.
Hyperglycaemic coma results when urinary losses are not
compensated.

Deficiency of insulin results in catabolism of proteins and fats.

Proteolysis results in removal of gluconeogenic amino acids from liver.
Catabolism of proteins and fats induces negative energy balance,
leading to increased appetite (polyphagia)

Diabetic Ketoacidosis

Serious complication of T1DM but can also occur in T2DM, although not as
commonly.
Marked insulin deficiency
Release of adrenaline blocks residual insulin action, and stimulates
secretion of glucagon.
Insulin deficiency lipoprotein lipase breakdown of adipose stores
free fatty acids. Oxidation of fatty acids in liver ketone bodies.
Rate at which ketone bodies are produced may exceed utilisation by
peripheral tissues, leading to ketonaemia and ketoneuria.
If urinary excretion of ketones is compromised by dehydration, systemic
metabolic ketoacidosis results.

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Diabetes - Complications

Infrequency of ketoacidosis and milder presentation in T2DM compared to

T1DM is due to higher portal vein insulin levels, which prevents
unrestricted hepatic fatty acid oxidation.

Other Metabolic Disturbances

Hyponatraemia: Osmotic diuresis causes Na and H20 loss, of which

polydipsia allows water to be resupplied but not sodium
Hyperkalaemia: the untreated diabetic would have hyperkalaemia, since
insulin usually drives potassium intracellularly.
Increased cholesterol levels: increased utilisation of fats by liver and it
deposits in vessel walls atherosclerosis
Body protein decrease: glucose cannot be utilised. Other stuffs like amino
acids and proteins need to be used up.
Low electrolytes due to diuresis.

AGEs deposit on basement membrane

o Causes basement membrane thickening
o Decreases negative charge of basement membrane
o Protein leaks through
Fructosamide
o Can be used in patients who have sickle cell issues or anaemia
o Especially in pregnant women, who have dilutional anaemia

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Diabetes - Complications

6. Describe the macrovascular and microvascular

complications of diabetes, with emphasis on
diabetic retinopathy and nephropathy. What
pharmacotherapy is indicated to slow down the
progression of these complications, and why?
Macrovascular

Atherosclerotic disease:
o CVD
AMI main cause of death
o Strokes (CVA cerebrovascular accident)
o Peripheral Vascular Disease
Can lead to gangrene
Hyaline arteriolosclerosis
o Amorphous hyaline thickening of arteriole walls
o Can occur without HTN.

Overall pathophysiology of complications of DM

1) Non-enzymatic glycosylation advanced glycosylation end

products (AGEs)
o Glucose attaches to proteins without aid of enzymes
This is related to HbA1C as marker for glucose in past 3
months
o Eventually forms AGEs which accumulate.
o AGE formation on proteins such as collagen causes cross linking
between polypeptides which can trap plasma and interstitial
proteins e.g.
LDLs are trapped in arteries leading to atheromas +
atherosclerosis
In capillaries such as glomeruli, albumin bind to basement
membrane causing thickening and leakage of proteins
2) Activation of protein kinase C
o Hyperglycaemia activates protein kinase C which activates:
Pro-angiogenic molecules (VEGF diabetic retinopathy)
Pro-fibrogenic molecules (transforming growth factor
B TGF-B) which lead to increased basement membrane
and ECM material deposition.
3) Intracellular hyperglycaemia increases susceptibility to
oxidative stress
o Only happens to tissues which do not rely on insulin for glucose
transport e.g. nerves, lens, kidneys and blood vessels.
o Metabolism of glucose consumes anti-oxidants which increase
susceptibility to oxidative stress.

Diabetic Nephropathy

3 results: Non-nephrotic proteinuria, nephrotic syndrome and chronic renal

failure

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Diabetes - Complications

Diabetes also affects arterioles causing hyalinising arteriolar sclerosis,

increasing susceptibility to pyelonephritis and papillary necrosis
Second to MI as cause of death from diabetes
3 lesions:
o Glomerular lesions
o Renal vascular lesions, principally arteriolosclerosis
o Pyelonephritis, particularly necrotising papillitis in diabetic
nephropathy

Morphological Changes

Capillary basement membrane thickening

o Widening of GBM occurs in all cases of diabetic nephropathy
o Thickening occurs progressively and concurrently with mesangial
widening and tubular basement membrane
Diffuse mesangial sclerosis
o Diffuse increase in mesangial matrix
o Mild proliferation of mesangial cells early in disease process
o Associated with overall thickening of GBM.
o As disease progresses, expansion can extend to nodular
configurations
o Leads to proteinuria
Nodular glomerulosclerosis
o Take form of ovoid nodules of matrix situated in periphery of
glomerulus
o Nodules show features of mesangiolysis with disruption of
mesangial/capillary lumen interface
o Individual nodules enlarge and may compress and engulf capillaries,
possibly obliterating glomerulus.
o Both afferent and efferent glomerular hilar arterioles show
hyalinosis.
o Kidney suffers from ischaemia, ATN and interstitial fibrosis,
undergoes contraction.
o Hyaline arteriolosclerosis affects both afferent and efferent
arterioles (which only usually occurs in diabetes).
Hyaline artioloslcerosis leads to narrowing of arterioles
RAAS activation
Exacerbation of kidney injury

Pathogenesis

Caused by metabolic defect, ie insulin deficiency, the resultant

hyperglycaemia, and glucose intolerance. Result in
o Increased collage type 4
o Fibronectin
o Increased ROS, which can damage glomerular filter
Nonenzymatic glycosylation of proteins
o Gives rise to advanced glycosylation end products which can
contribute to glomerulopathy
Haemodynamic changes
o Early diabetic nephropathy characterised by increased GFR,
increased glomerular capillary pressure, glomerular hypertrophy
and increased glomerular filtration area.

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Diabetes - Complications

All this contributes to loss of podocytes, which can undergo apoptosis in

response to metabolic abnormalities and expose to ROS

Diabetic Retinopathy

Key idea is basement membrane thickening

Diabetic capillaries tend to become more leaky than normal to plasma
proteins.
Ocular involvement may include retinopathy, cataract formation or
glaucoma.
Approximately 60-80% of patients develop some form of diabetic
retinopathy 15 20 years after diagnosis.
Lesion of retinopathy: attributable to hypoxia-induced overexpression of
VEGF (protein which stimulates vasculogenesis and angiogenesis) in the
retina.
Treatment is intravitreous injection of anti-angiogenic agents

Classification

First stage: non-proliferative diabetic retinopathy

o No symptoms, 20/20 vision
o Can only detect via fundoscopy, which will visualise
microaneurysms
o Ischaemia can also be noted by narrowing of blood vessels
Macular oedema
o Blood vessels leak fluid and lipids into macular region
o Blurred vision and darkened due to swelling macular
Second stage: proliferative diabetic retinopathy
o Abnormal new blood vessels (neovascularisation) form at back of
eye
o These can burst and bleed and blur the vision (vitreous
haemorrhage), resulting in blurred vision, because new blood
vessels are fragile.
o See haemorrhage, cotton wool spots (nerve damage)
o Haemorrhages often happen during sleep

Pathophysiology

Hyperglycaemia induced intramural pericyte death and thickening of

basement membrane lead to incompetence of vascular walls
Changes formation of blood-retinal barrier and retinal blood vessels
became more permeable.
Hypoxia implicated as causative factor in degradation of retina
Small blood vessels can be damaged by over-accumulation of glucose
and/or fructose damages the tiny blood vessels in retina

Proliferative diabetic retinopathy

Blood vessel proliferation

Lack of oxygen in retina causes fragile, new blood vessels to grow
Fibrovascular vascularisation can cause retinal detachment

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Diabetes - Complications

Blood vessels can grow into anterior chamber of eye and cause
neovascular glaucoma.

Management

Laser treatment
Injection of corticosteroids/ anti-VEGF agents into eye
o Triamcinolone
Decreases macular oedema, increase in visual acuity
3 months every injection
o Bevacizumab (anti-VEGF)
Reduces diabetic macular oedema
Vitrectomy
o Done when theres a lot of blood in the vitreous
o Remove cloudy vitreous and replace with saline solution
o Done under local. Incision in sclera, eye patch for a few days

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Diabetes - Complications

7. Discuss the factors that may result in the

development of a foot ulcer in an individual with
diabetes mellitus.
Diabetic Neuropathy
Classifications

Polyneuropathy, mononeuropathy, radiculopathy and autonomic

neuropathy
o Polyneuropathy/mononeuropathy
Most common form distal symmetric polyneuropathy
o Diabetic polyradiculopathy
Pain in distribution of one or more nerve roots
May be accompanied by nerve weakness
Self limited, resolve in 6-12 months
o Mononeuropathy
Presents with pain and motor weakness in distribution
of one single nerve
Occur commonly at entrapment sites such as carpal
tunnel
o Autonomic Neuropathy
Signs of autonomic dysfunction involving cholinergic,
noradrenergic, and peptidergic (peptides such as substance
P) systems
Can affect any system
Cardiovascular:
o Resting tachycardia
o Orthostatic hypertension
Gastroparesis, bladder emptying abnormalities
Anhydrosis of the feet can promote dry skin with cracking,
increasing the risk of foot ulcers

Symptoms

Sensation of numbness, tingling, sharpness, or burning that starts in the

feet and spreads proximally.
Neuropathic pain develops in some individuals
o Acute pain
Lasts <12 months
Sometimes treatment related, occurring in context of
improved glycaemic control
As diabetic neuropathy progresses, pain subsides and
eventually disappears, but sensory deficit persists.
Physical exam: loss of ankle deep tendon reflexes, sensory
loss, and abnormal position sense.

Foot Ulcers

Contributing factors:
o Diabetic neuropathy
o Abnormal foot biomechanics
o Peripheral vascular disease

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Diabetes - Complications

Motor neuropathy:
o Imbalance between flexion and extension Deformity (hammer
toe, claw toe)
o Foot deformities due to abnormal weight bearing while walking
o Bony prominences, pressure points > ulcers

Pathophysiology of Foot Ulcers

Altered metabolism
o Altered protein and lipid metabolism abnormal granulation tissue
formation
o Advanced glycation end products form on ECM with slow turnover
rate
o Alter the properties of collagen, laminin via cross linking on Type 1
collagen and elastin
Changes to fibroblast
o Fibroblasts from diabetic ulcers have decreased ECM protein
production and delayed wound contraction and impaired wound
healing.

Risk Classification
Group 0
No evidence of neuropathy

Group 1
Neuropathy present but no evidence of foot deformity or peripheral vascular
disease

Group 2
Neuropathy with evidence of deformity or peripheral vascular disease

Group 3
History of foot ulceration or lower extremity amputation

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Diabetes - Complications

8. List the microorganisms most commonly

associated with foot ulcers in a diabetic patient
and outline the treatment strategy that you
would recommend.
Microorganisms

Most are polymicrobial

Superficial diabetic foot infections
o Aerobic gram positive cocci
MRSA, coagulase negative strep
Deep, chronically infected ulcers
o Enterococci, Pseudomonas Aeruoginosa, Enterobacteria
Wounds with extensive local inflammation, necrosis, and gangrene
o Anaerobic organisms
Anaerobic streptococci
Bacteroides
Clostridium species

Antibiotics
First-line

Alternative

Mild-moderate
At least 5 days

amoxycillin+clavula
nate 875+125 mg
orally, 12-hourly

Severe limb- or lifethreatening

infection

piperacillin+tazobac
tam 4+0.5 g IV, 8hourly

cephalexin 500 mg
orally, 6-hourly PLUS
metronidazole 400
mg orally, 12-hourly
ticarcillin+clavulanate
3+0.1 g IV, 6-hourly

Penicillin
hypersensitivity
ciprofloxacin 500 mg
orally, 12-hourly PLUS
clindamycin 600 mg
orally, 8-hourly.
ciprofloxacin 400 mg
IV, 12-hourly OR
ciprofloxacin 750 mg
orally, 12-hourly
PLUS clindamycin 900
mg IV, 8-hourly (slow
infusion required)

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Diabetes - Complications

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Diabetes - Complications

9. Discuss the nature and pathogenesis of

neurological lesions seen in long-standing
diabetes mellitus.

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Diabetes - Complications

10. What pharmacotherapies are available for type

1 and type 2 diabetes? Why do the treatments
differ?
Goals of Therapy
1) Eliminate symptoms related to hyperglycaemia
2) Reduce or eliminate long term micro and macrovascular complications of
DM
3) Allow patient to achieve as normal a lifestyle as possible

Diabetes Type 1
Lifestyle

Meals/ Diet
o Estimate how much carbs they are about to consume
o Patient should attempt to maintain consistent carbohydrate profile
daily
o Or patients could use carb : insulin ratios so they dont need to take
a fixed amount of carbs daily
Monitoring of blood glucose levels
o Self-testing done 4 7 times daily
Exercise
o Avoids weight gain
o Hypoglycaemia may occur after vigorous exercise
o Monitor blood glucose levels before during and after exercise
o Delay exercise if blood glucose >14mmol/L and ketones present
o If blood glucose <5.6mmol/L ingest carbs before

Glycaemic targets

Aim for HbA1C of <7%, set at 8% for older patients and those with
comorbidities or limited life expectancy

Insulin

Administer basal level of insulin

o Delivered by daily or twice daily injections of intermediate or longacting insulin preparation,
OR
o Continuous delivery of subcut rapid insulin preparation via a pump
+ premeal bolus of short or rapid acting insulin.
Dose of premeal bolus determined by blood glucose level
premeal, size and composition of the meal, and anticipated
activity levels.

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Diabetes - Complications

Choice of insulin regimen

Choice between multiple daily injections or continuous subcut delivery of

rapid insulin prep via a pump is matter of patient prep and lifestyle.
Basal insulin
o Insulin Glargine
o NPH
o Detemir
Prandial insulin
o Regular
o Lispro
o Aspart
o Glulisine
Most newly diagnosed T1DM given total daily dose of 0.2 0.4 units of
insulin/kg/day, although most will ultimately require 0.6-0.7 units of
insulin/kg/day.
Approximately one half of total dose should be given as a basal insulin,
either once or twice daily.
o Remainder given as short or rapid acting insulin post/pre prandial.

Type 2 Diabetes

Lifestyle changes
o Exercise to promote insulin sensitivity and weight loss

Glucose Lowering Agents

Increase insulin secretion

Reduce glucose production

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Diabetes - Complications

Increase insulin sensitivity

Enhance GLP-1 action
Promote urinary excretion of glucose

Apart from glucosidase inhibitors and amylin analogue, glucose lowering

agents are useless in DM1, and shouldnt be used for glucose management of
severely ill DM2.
Biguanide
Metformin
Reduces hepatic glucose production and improves peripheral glucose
utilization slightly
Activates AMPK
Reduces hepatic gluconeogenesis by preventing glucagons ability to
generate cAMP in hepatocytes.
Extended release form of metformin fewer GI symptoms, diarrhea,
anorexia, nausea and metallic taste.
Lactic acidosis can occur but is rare
B12 levels lower during treatment, and metformin should not be used in
people with renal insufficiency, CHF, any form of acidosis, liver disease or
severe hypoxaemia.
GFR >30, and lowered dose when GFR <45
Insulin Secretagogues
Interacts with ATP sensitive potassium channel on cell
Most effective in patients with t2DM <5 years who have residual
endogenous insulin production.
First generation sulphonylureas
o Chlorpropamide, tolbutamide
o Longer half life
o Greater incidence of hypoglycaemia
o NO LONGER USED
Second generation sulfonylureas
o Glemepiride, glipizide
o Rapid onset of action and better coverage of postprandial glucose
rise
o Shorter half life, may require more than once a day dosing
o Reduce fasting and postprandial glucose
o Initiated at low doses, increased at 1 to 2 week intervals
o Immediate action, should be taken before a meal
o Hypoglycaemia
Delayed meals, increased physical activity, alcohol intake,
renal insufficiency
Most sulfonylureas metabolized in liver and cleared by
kidney, hence hepatic or renal dysfunction not advised
GLP-1 Receptor Enhancing
Incretins
Incretins amplify glucose stimulated insulin secretion
Glucagon like peptide 1

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Diabetes - Complications

Do not cause hypoglycaemia because of glucose dependent nature of

incretin-stimulated insulin secretion
o Hypoglycaemia only occurs when there another drug e.g.
sulfonylureas
Exenatide is example of incretin
Increase glucose stimulated insulin secretion, suppresses pancreatic
glucagon release, and slow gastric emptying.
Most patients experience weight loss and appetite suppression (satiety by
action upon hypothalamus).

DPP-IV inhibitors
Inhibit degradation action of DPP-IV on native GLP-1, enhancing the
incretin effect
DPP-IV usually expressed on cell surface of endothelial cells and some
lymphocytes
DDP-IV inhibitors promote insulin secretion in absence of hypoglycaemia
GLP-1 drugs (incretin) however produce greater GLP-1 action than DPP-IV
inhibitors
glucosidase inhibitors
Reduce postprandial hyperglycaemia, even with T1DM
Taken before each meal
Prevents cleavage of large oligosaccharides into simple sugars
Major side effects are diarrhoea, flatulence, abdo distension due to
increased delivery of oligosaccharides to intestinal gut
Thiazolidinediones aka glitazones
Bind to PPAR- nuclear receptor
PPAR- most expressed in adipocytes
PPAR- promotes adipocyte differentiation, reduced hepatic fat
accumulation and increased fatty acid storage.
Circulating insulin levels decrease, indicating reduction in insulin
resistance.
Rosiglitazone raises LDL, HDL, and triglycerides slightly
Proglitazone raises HDL to greater degree, and LDL a leser degree, but
lowers triglycerides.
Associated with weight gain, peripheral oedema and CHF
Contraindicated in patients with liver disease or CHF
Sodium-Glucose CO-Transporter 2 Inhibitors (SLGT2)
Lower blood glucose by inhibiting co-transporter in PCTs of kidney.
Inhibits glucose reabsorption and increased glucose excretion.
Limited clinical experience
Urinary/vaginal infections more common due to increased urinary glucose
Insulin Therapy
Insulin should be considered as initial therapy in T2DM with lean
individuals or those with severe weight loss, or in individuals with
underlying renal or hepatic disease
Usually initiated with single dose long acting insulin (0.3-0.4units/kg/day)
NPH, glargine or detemir

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Diabetes - Complications
Choosing correct initial glucose lowering agent
Insulin secretagogues, biguanides, GLP-1 Receptor agonists, and
thiazolidinediones more effective than glucosidase inhibitors, DPP-IV
inhibitors and SLGT2 inhibitors.
Fast plasma glucose lowering: insulin secretagogues, GLP-1 Receptor
inhibitors, DPP-IV inhibitors, -glucosidase inhibitors and SLGT2
Slower (delayed by weeks): Biguanides, thiazolidinediones
Metformin usually given firs to meet glycaemic target or if max dose
reached, and then either insulin secretagogue or DPP-IV inhibitor used

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Diabetes - Complications

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Diabetes - Complications

11. Explain the importance of ongoing monitoring

of blood glucose levels in diabetes.

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Diabetes - Complications

Glucocorticoids

Increase insulin resistance

Decrease glucose utilisation
Increase hepatic glucose production
Impair insulin secretion