Diabetes

Diabetes Mellitus: Systemic Overview

· WHO definition – diabetes mellitus (DM) is a metabolic disorder of multiple aetiology characterised by chronic
hyperglycaemia with disturbances of carbohydrates, fat, and protein metabolism resulting from defects in insulin
secretion, action, or both.
· Diabetes mellitus leads to:
o Hyperglycaemia
o Excess urine and thirst
o Blurred vision
o Unexplained weight loss
o Lethargy
· Diabetes mellitus results in:
o Long term damage or failure of organs specifically, the eyes, kidneys, nerves, heart, and blood vessels.
· Types of diabetes mellitus:
o Type 1
 Insulin-dependent
 Results from diminished production of insulin
 Juvenile-onset
o Type 2
 Non-insulin dependent
 Results from impaired production and action of insulin.
 Adult-onset
o Gestational diabetes
 Onset during pregnancy
 Impaired glucose tolerance
o Genetic syndrome affected pancreas
o Endocrinopathies
o Pancreatic disease or cancer

Diabetes Mellitus: Systemic Epidemiology

· Affects 422 million individuals worldwide and this number is expected to double in the next 20 years
· Type 1 DM:
o ~10% of cases
· Type 2 DM:
o ~85 – 90% of cases
o Affecting 20% of the population over 65 years
o 10%+ of the health budget in many countries is used for Type 2 DM care

Diabetes Mellitus: Normal Glucose Metabolism

· Basal or fasting glucose metabolism
o Under basal conditions
 ~50% of glucose is used by the brain
 Insulin independent
 ~25% of glucose is used by the liver or gastrointestinal tissues
 Insulin independent
 ~25% of glucose is used by the muscle
 Insulin dependent
o Hepatic glucose production: the liver produces glucose from glycogen to meet the needs of the brain and
other tissues. The liver has glycogen stores (stores of glucose).
o Other sources of glucose production:
 Adipose breaks down fat stores to release free fatty acids
 The muscle can use its own glycogen or free fatty acids
· Islets of Langerhans
o Small endocrine glands located in the pancreas
o Four types:
 α -cells synthesise glucagon
  β -cells synthesise insulin
· Following glucose ingestion there is an/a:
o Increase in plasma glucose levels
o Stimulation of insulin release
o Inhibition of glucagon release
· Insulin acts on various tissues:
o Muscle – to increase glucose uptake and promote glycogen and protein synthesis from glucose

o Adipose (fat) – to increase glucose uptake, promote lipid synthesis from glucose, and decrease lipid
breakdown
o Liver – to decrease glucose production, and promote glycogen and lipid synthesis from glucose
· Process:
o Insulin binds to specific receptors on the cell surface.
o Secondary messengers initiate a signal cascade to stimulate glucose uptake.
o A drop in blood glucose level leads to decrease release of insulin.

Diabetes Mellitus: Type 1

· Aetiology:
o Autoimmune destruction of β -cells that produce insulin leading to insulin deficiency. Insulin deficiency
causes hyperglycaemia as:
 Muscle and adipose tissue cannot respond to glucose ingestion
 Liver and adipose tissue continue to produce glucose despite ingestion.
o Occurring in genetically predisposed individuals
 Major locus: human leukocyte antigen (HLA) contributes to genetic susceptibility to type 1 DM. Genes
in HLA are reported to account for a 50 – 60% genetic risk.
 HLA genes affects HLA protein binding to antigenic peptides and antigen presentation to T cells
· Pathophysiology:
o Environmental factors trigger an autoimmune response
 Viral, other infections, and/or altered intestinal microbiome
 Timing of exposure is critical based on the early onset nature of type 1 DM
o Autoimmune response:
 Activation of T cells reactive to islet cell antigens
 T cells destroy islet cells resulting in insulin deficiency
o New theories/ ideas:
 Events leading to Type 1 DM occur in utero
 β cell loss is not linear (continuum) and β cells still remain in longstanding disease.
· Work-up:
o Blood glucose test – provides a snapshot of hyperglycemia.
 Random: 11.1 mmol/L or higher
 Fasting: 7.0 mmol/L or higher
o Glycosylated haemoglobin test (HBA1C) – reflects long term blood glucose control.
 % of blood sugar attached to haemoglobin
 HbA (haemoglobin) stay glycosylated (1C) until they degrade (approx. 3 months)
 Indicates blood glucose control over a long period of time
 Only confirmed indicator to estimate risk of developing diabetic complications
 HbA1C of 7% or higher on two separate tests
o Additional tests:
 Blood test to check for antibodies
 Urine test for ketones
· Management:
o Traditional: finger prick tests + insulin injections several times a day
o New technologies: continuous glucose monitors which take readings every 5 minutes.
o Insulin pump:
 Delivers insulin via catheter under the skin continuously over 24 hours
 Uses less insulin and mimics normal insulin production
 During meals, the pump can be programmed to provide extra insulin
 The downfall is that it is costly and can lead to associated weight gain and infection at the cannula site.
o Insulin analogues: genetically altered to be more rapid or more uniforming acting.

o Combinations:
 Ultra-long-acting insulin + rapid acting insulin analogue e.g., Ryzodeg 70/10
 Administered once daily with main carbohydrate meal

Diabetes Mellitus: Type 2

· Aetiology: involves insulin resistance which causes insulin overproduction and overtime this leads to β -cell
dysfunction; defects in the insulin pathway.
o There are many risk factors (genetic and environmental) but the exact pathogenesis remains unclear.
o Insulin resistance seems to be related to defects in insulin receptors on cells or other proteins in the insulin
signalling pathway.
o Even though the absolute levels of insulin may be high in type 2 DM individuals, they are low relative to the
individual’s needs.
· Pathophysiology:
o Defects in insulin receptor or post-receptor elements leading to insulin resistance. Defects include:
 Decreased number of insulin receptors
 Decreased tyrosine kinase activity (secondary messenger)
  Decreased glucose transporter activity
 Decreased glycogen production
o Insulin resistance leads to:
 Poor uptake of glucose by muscle and adipose
 Poor suppression of hepatic glucose production
 Impaired lipid uptake by adipose tissue
o β cells increase insulin production to compensate for poor glucose uptake. Eventually β cells deteriorate
leading to insulin deficiency. Deterioration occurs because of exhaustion (burnout), glucotoxicity, and/or
amyloid deposition.

· Risk factors:
o Overweight/ obesity
o Physically inactive
o Hypertension
o Low high-density lipoprotein (HDL) or high trigylcerides
o Age, 45 or older
o Family history
o History of gestational diabetes
o Ethnicity – African American, Hispanic, Pacific Islander

· Diagnosis: blood glucose tests, HbA1C

· Treatment:
o Lifestyle modifications – diet and exercise
o Oral hypoglycaemic medication
 Biguanides (metformin) e.g., Diabex, Diaformin
 1st line
 Reduces hepatic glucose production
 Increases peripheral use of glucose
 Sulfonylureas – increases insulin secretion e.g., gliclazide (Diamicron)
 SGLT2 – inhibits SGLT2, reducing glucose reabsorption by the kidney e.g., empagliflozin (Jardiance,
Jardiamet)
 Fibrates – unknown lipid lowering effect.
o Non-insulin injectables
 Glucagon-like peptide (GLP-1) analogues
 Signals the hypothalamus to decrease food intake (feeling full)
 Increases glucose-dependent insulin secretion from pancrease
  E.g., Bydureon and Byetta (exenatide) – derived from the saliva of a lizard (gila-moster),
Dulaglutide – consists of GLP-1 (7 – 37) covalently linked to an Fc fragment of human IgG4,
Victosa (liraglutide) – derivative of a human incretin (metabolic hormone).
o Insulin therapy
 Insulin-sensitising agents e.g., thiazolidinediones, biguanides
 Insulin stimulators e.g., sulfonylureas, GLP-I analogues, DPP 4 inhibitors
 Insulin-dependent hypoglycaemia agents e.g., SGLT2
Note, a patient on insulin does not necessarily have type 1 DM. Insulin may be added into the tx for
a type 2 DM to improve their overall glycaemic control.
o Combination therapy
o Blood pressure management
o Blood lipid management
· Nearly 50% of Australians with DM are not at the target HbA1c. Reasons include:
o Therapy not initiated at the correct time or being optimised early.
o Reluctance to initiate to injectable therapy.
o Reluctance to intensify to insulin treatment.
o Not rechecking HbA1c – should be performed every 3 to 6 months
o Suboptimal patient adherence e.g., running out of medication or dropping specific medications
o Healthcare delivery systems.

Diabetes Mellitus: Gestational

· Aetiology: onset during pregnancy; placental hormones block insulin during pregnancy. If insulin resistance
already exists, the body cannot cope with the extra demand for insulin, leading to hyperglycaemia.
o Risk factors: older age, family history of DM, high BMI, certain ethnicities
o Occurs in 14 – 16% of pregnant women
o Patients are not at risk of developing DM-related retinopathy
· Management: diet, physical activity, monitoring blood glucose levels and insulin.
o Most resolved following birth however, the risk of the mother and baby developing type 2 DM in later life is
increased.

Diabetes Mellitus: Complications

· Complications include:
o Cardiovascular/ coronary artery disease – macrovascular
o Peripheral arterial disease – macrovascular
o Neuropathy – microvascular
o Nephropathy (kidney) – microvascular
o Retinopathy – microvascular
o Foot damage
o Skin conditions
o Hearing impairment
o Alzheimer’s disease
o Stroke – macrovascular
o Depression
· Pathophysiology of diabetes complications:
o Longstanding hyperglycaemia activates/ alters many cellular pathways
 Increased reactive oxygen species (ROS) formation from activation of mitochondrial electron-transport
chain
 Activation of the polyol pathway
 Activation of the hexosamine pathway
 Activation of protein kinase C
 Increases production of advanced glycation end products (AGEs)
 Longstanding hyperglycaemia leads to glycosylation of proteins
 Over time glycosylated proteins become advanced glycation end products (AGEs)
 AGEs can lead to oxidative stress, changes in haemodynamic, and initiation of the inflammation
cascade
 o Pathways defects lead to development of microvascular and macrovascular complications via
 Endothelial dysfunction and altered haemodynamic and perfusion properties
 Tissue ischaemia and oxidative stress
 Inflammation and immune responses

o AGEs and retinopathy – diabetic related damage to the blood vessels of the retinal.
 Role of AGEs:
 Increase vessel permeability causing leakage and breakdown of the blood-retinal barrier
 Increase vascular stiffness
 Upregulate VEGF which stimulates angiogenesis and neovascularisation
o AGEs and nephropathy – diabetic related damage to the kidney which leads to haemodynamic changes
(hyperfiltration and hyperperfusion), proteinuria, poor glomerular filtration rate and eventually renal failure.
 Role of AGEs:
 Reduce glomerular filtration capacity by altering normal structure of ECM proteins and basement
membrane permeability
 Stimulate growth factors and cytokines which induce hyperfiltration and hyperperfusion
o AGEs and neuropathy – diabetic induced nerve damage. Typically, affects peripheral tissues e.g., legs and
feet.
 Role of AGEs:
 Modified axon proteins leading to nerve fibre atrophy
 Increased micro vessel permeability and reduced nerve blood flow, inducing hypoxia.

Diabetes Mellitus: Ocular

Diabetes & Vision Loss
Major causes of vision loss in diabetes
1. Diabetic Macula Oedema
· Untreated diabetic macula oedema (DME) is the major cause of moderate vision loss in people with diabetes
· Abnormal accumulation of excess fluid within the extracellular spaces of the neurosensory retina due to
breakdown of the blood-retinal barrier
2. Vitreous or Preretinal Haemorrhage

3. Tractional Retinal Detachment (in proliferative DR)

 · New vessels can produce fibre scaffolding which may retract and pull the retina off
4. Diabetes Macula Ischaemia (DMI)
· Visual acuity loss may occur in cases of moderate to severe DMI
· DMI is difficult to detect with fundoscopy. Historically, fluorescein angiography was used in cases of
unexplained VA loss and to diagnose DMI.
· OCT angiography is a new method which enables optometrist to quickly and non-invasively assess for
diabetic macula ischaemia.

Enlargement of the foveal

avascular zone (FAZ)

Paramacular capillary
non-perfusion

Diabetes Retinopathy Snapshot

· DR is the leading cause of preventable vision loss in working age adults
· DR is the most frequent cause of new blindness in individuals aged 20 – 74 years in developed countries
· Global prevalence of diabetic retinopathy is ~34.6%
o 1 in 10 of these individuals had vision threatening diabetic retinopathy
· Blue Mountains Eye Study (1992-1994)
o Of the participants >49 years with diabetes:
 32.4% had diabetic retinopathy
 4.3% had vision threatening macular oedema
 1.6% had proliferative diabetic retinopathy
· National Indigenous Eye Health Survey (2009)
o 36% of people with diabetes had diabetic retinopathy
· National Eye Health Survey (2016)
o Only 78% of non-Indigenous and 53% of Indigenous people had received the NHMRC recommended
biannual diabetes eye check
· Diabetic retinopathy is typically asymptomatic when most treatable
o 98% of severe vision loss is preventable with early detection and treatment

Broad Rule of Thumb

1/3 of patients with diabetes have diabetic retinopathy
1/3 of those patients have vision threatening diabetic retinopathy

Other Ocular Conditions Associated with Diabetes

· Refraction and accommodation shifts
o Refractive error changes
 Osmotic changes to the cortex – the lens thickens
 Transient hyperopic change in the patient receiving improved control after hyperglycaemia
o Reduced amplitude of accommodation found in young individuals with type 1 DM
· Colour vision defects
o Blue-yellow or red-green defects may precede diabetic retinopathy development
o The level of 100 Hue change correlates with the level of diabetic retinopathy
· Pupil miosis and sluggish reactions
o Sluggish reactions, miotic, and weaker reaction to mydriatics
o Consider dilating with tropicamide and phenylephrine if indicated
· Neovascular Glaucoma
o Fibrovascular network of vessels grows over the angle structures leading to IOP increase and secondary
glaucoma
o Iris rubeosis is usually first observed at the pupil margin. However, neovascular vessels may infiltrate the
angle without any vessels visible on slit lamp examination.
o Gonioscopy is indicated when the IOP is elevated or asymmetrical.

· Primary Open Angle Glaucoma

o Studies provide conflicting evidence on whether diabetes mellitus is a risk factor for POAG
 Systematic review (Zhao D., Ophthalmology 2015) showed that diabetes, diabetes duration, and fasting
glucose levels were associated with a significantly increase of glaucoma and that DM is associated with
increased IOP
o Glaucomatous optic neuropathy may be influenced by:
 Lower retrobulbar flow in the central retinal artery
 Higher retinal microcirculation flow
 Concomitant systemic hypertension affecting vascular perfusion of the optic nerve head
 Formation of AGEs in the trabecular meshwork and lamina cribrosa
· Cataract
o Hyperglycaemia and diabetes duration are risk factors
 o Tends to develop earlier and progress more rapidly
o Increased prevalence of posterior subcapsular cataracts and cortical cataracts (+ nuclear sclerosis in type 2
DM)
o Reversible lens opacities and snowflake opacities – may go away with appropriate control
o Deposition of advanced glycosylation end-products is a postulated mechanism
· Cornea
o Impaired corneal wound healing
 Higher risk of SPK, RCE/ epithelial basement membrane disorders, persistent epithelial defects,
endothelial dysfunction, and corneal nerve impairment
o Reduced corneal sensitivity due to neuropathy of the ophthalmic division of the trigeminal nerve
 May reduce reflex tear secretion and subjective symptomatology
 Alters tear chemistry
 May increase risk of neurotrophic keratitis
o Contact lens-related microbial keratitis
 Avoid extended wear
· Anterior Eye
·
· Cranial nerve palsies
· Visual field defects
· Posterior vitreous detachment
· Vitreous degeneration
· Iris depigmentation
· Tear film anomalies/ lacrimal gland damage
· Higher IOP
· Conjunctival microaneurysms
· Accommodative dysfunction
· NAAION
· Papillopathy