DIABETES MELLITUS

A condition characterized by chronic hyperglycemia due to lack of insulin as a result

of autoimmune destruction of the beta cells of the islet of langerhans of the
pancreas or reduced beta release of insulin with or without insulin resistance

Causes/ risk of diabetes

• autoimmune destruction of the beta cells
• Reduced production of insulin

• Pancreas causes
◦ Pancreatitis ( incl. viral infections, mumps, coxsackie, rubella, enterovirus,
alcohol)
◦ Pancreatectomy ( > 90% of the pancreas)
◦ Pancreatic cancer

• Drugs : Anti- tb drugs

• hemochromatosis
• Cystic fibrosis
• Cushing syndrome
• Glycogen storage diseases ( Gaucher’s disease)

Autoimmune causes
• Addison’s diseases
• Graves’ disease
• Hashimoto’s thyroditis

Functions of insulin
considered as the only anabolic hormone in the body

• it converts glucose to glycogen for storage

• Protein synthesis
• Lipid synthesis
• Enhances cellular(hepatic) uptake of glucose for atp production ( glycolysis)
Types of diabetes mellitus

type 1 diabetes mellitus

◦ Formally known as insulin dependent, however it has been noted that type 2
diabetes may require insulin as well, making the terminology obsolete
◦ Due to the autoimmune destruction of the beta cells of the islet of
langerhans

Features
• onset
◦ befor puberty / adolescent age
• Symptoms
◦ 3 Ps : polydipsia, polyphagia, polyuria
◦ Unexplained weight loss
• HLA association : HLA DR3 +/- DR4
• Concordance is identical twins : app. 30% -> environmental influence
• Associated with autoantibodies such as islet cell antibodies ( ICA), anti-glutamic
acid decarboxylase antibodies ( anti-GAD antibody)
• Persistent hyperglycemia unresponsive to diet modifications and oral
hypoglycemic medications

Latent autoimmune diabetes in adults ( LADA) is a variant of type 1 dm which has a

slower progression to insulin dependence

Biochemical evidence of diabetic ketoacidosis

• ketonemia -> keto acidosis
• Ketouria
• C- peptide levels are low

Type 2 diabetes mellitus

• formally known as non insulin dependent diabetes mellitus. Same reason it was
changed as type 1
• Due to decreased insulin production with or without insulin resistance
Features
Onset
• usually after 40 years
• Mostly asymptomatic / usually realized with complications eg Silent MI
• No HLA association
• Concordance in identical twins is > or = 80% -> indicates greater genetic influence
• no association with antibodies

• NB - has a variant known as maturity onset diabetes of the young ( MODY) ,

which is a rare autosomal dominant type or form of type 2 DM, that occurs in
young people

biochemical evidence
• ketonaemia and ketouria are possible but rare/ uncommon
• C peptide levels are normal

WHO diagnostic criteria for diabetes mellitus

NB- symptoms of hyperglycemia : polyuria, polydipsia, polyphagia, unexplained weight

loss, blurred vision, lethargy

There are three criteria, any of which is diagnostic :

1. Symptoms of hyperglycemia PLUS raised blood glucose on a single occasion
( FBS >/= 7.0mmol/l or RBS >/= 11.1mmol/l )
2. Raised venous glucose on 2 separate occasions, either by
a. FBS >/= 7.0 mmol/l
b. RBS >/= 11.1mmmol/l
c. Oral glucose tolerance test ( OGTT) with 75 g of anhydrous glucose : 2h
RBS >/= 11.1 mmol/l
3. Glycated hemoglobin ( HbA1C)
a. HbA1C > 6.5 % ( > 48 mmol/mol)
represents the amount glucose bound to hemoglobin over a period of three
months

Glycated hemoglobin should not be checked in

• pregnant women
• Type 1 diabetic patients
• Patients with hemoglobinopathy
• Children( less than 6 months, ie infants )

• it measures the concentration of glucose on the HbA1 hemoglobin, ie, the more
hbA1, the higher the value and vice versa
• In pregnant women there is an increased cellular volume
• In infants , less than 6 months, there is less HbA1 because of the HbF
• In type 1, it is always high

Oral hypoglycemic agents

Biguanides
• metformin

Mechanism
• decreases hepatic output of glucose
• increases sensitivity of hepatic cells to insulin ( peripheral intake of glucose

Side effects
• Nausea
• Abdominal pain
• Diarrhea
• Weight loss
• Lactic acidosis ( if eGFR </= 36ml/min/1.73m2)

Sulfonylureas
1st generation : acetohexamide, chlorpropamide , tolazamide, tolbutamide
2nd generation : glibenclamide / gliburide , glipizide, gliclazide, glimepiride
Mechanism
• Increases the beta cell release of insulin : blocks potsssium channels, reducing its
influx and increasing influx of calcium into the cell resulting in its depolarization
and subsequent release of insulin

Side effect
• hypoglycemia
• Weight gain

Sulfonylurea receptor binders / meglitinide

• Nateglinide
• Repaglinide

Mechanism of action
• Cause the beta release of insulin

Side effect
• hypoglycemia
• Weight gain

Thiazolidinediones / Glitazone
• Pioglitazone. Rosaglitazone

Mechanism
• increase insulin signaling and hence insulin sensitivity by activating the PPAR
( peroxisomal proliferator activated receptors gamma and alpha )

Side effect
• Fluid retention
• Deranged LFTs
• Fractures
• Hypoglycemia

Glucagon like peptides ( GLP-1) agonist

• Incretins : located in the gut, cause a glucose dependent insulin release by the
 beta cells
• Incretins are synonymous to naturally occuring glucagon like peptide
• Produced by brush border cells of small intestines
Eg of GLP agonist : exenatide, liraglutide

MOA : they help in stimulation/ function of incretins

Side effects
• hypoglycemia

Dipeptidyl peptidase- 4 - inhibitor ( gliptins )

MOA
They stop the breakdown of incretin because of DPP-4 causes degradation of
incretin in effect causing increase of insulin hence the inhibitors block that function
Eg. Sitagliptin , saxagliptin, vildagliptin

Side effect : hypoglycemia

Note : does not cause weight hair hence more preferred to sulfonylureas in obese
people

Alpha glucose dose inhibitor

Alpha glucosidase helps in the breakdown of carbohydrates to glucose

MOA
Blocks alpha glucosidase hence reducing the breakdown of carbohydrates to glucose
Eg acarbose , miglitol

Note : the alpha glucosidase inhibitors delay gastric emptying hence delay appetite
satiety

Side effect
Nausea and vomitting ( most cmmon )
Anorexia
Flatulence
GI upset
Bloating
Abdominal pain

Selective sodium glucose co transporter 2 inhibitor ( gliflozin )

Eg. Empaglifiozin , dapaglifiozin

MOA
Usually used in cardiac and renal associated pathologies
Transport glucose and sodium into the cells with ca 2+ causing depolarisation
causing insulin release
Usually given with metformin

Insulin Secretagogues
• Thiazolidenediones/ glitazone
• Sulfonylurea
• Sulfonylurea receptor binders

Insulin sensitizers
• Thaiazolidinediones
• Biguanides

Impaired glucose tolerance ( IGT) and impaired fasting glucose ( IFG)

They are precursor to diabetes

IGT : for impaired glucose tolerance

• FBS : 70 mmol/l
• RBS : >/= 7.8 mmol/l but 11.1 mmol/l

IFG
• For impaired fasting glucose
• FBS : >/= 6.1 mmol/l but 7mmmol/l

Note : impaired glucose tolerance has a higher progression to diabetes than impaired
fasting glucose ( IFG)
For IGT and IFG , lifestyle modifications is the first line of treatment

Syndrome X
• defined by the international diabetes federation as : central obesity ie BMI > 30
kg/m2 or increased waist circumference in males > 94cm , and in females > 80cm
plus any two of the following
• BP > 130/85 mmHg
• Triglycerides >/= 1.70 mmol/l
• HDL </= 1.03 mmol/l ( males ) and 1.29 mmol/l ( females )
• FBS >/= 5.6 mmol/l
• Type 2 DM

Dawn Phenomenon
• short acting insulin is given at night and long acting given during the day
• Patient is given short acting insulin at night and its effect is reduced in the
morning

At dawn patient releases peak levels of center insulin regulatory hormone

• Glucagon , cortisol , adrenaline , catecholamines , growth hormone

This means these enhance gluconeogenesis and in effect chase hypoglycemia

Somogyi effect
At midnight there is hypoglycemia
Also known as rebound hyperglycemia
Excess dose of insulin is administered in the evening the breaks down glucose and by
midnight causes hypoglycemia
In response to the hypoglycemia at dawn, counter insulin regulatory hormones are
secreted leading to hyperglycemia by morning

Draw table with insulin drugs and their peaks.

Type 2 DM treatment
1st line of treatment
• life style modifications : diet, exercise and weight loss
• Then add metformin metformin

• 16 weeks later, if hbA1c >/= 53 mmol/mol, add sulfonylurea eg glicazide

◦ Replace sulfonylurea with gliptins if BMI >/= 35kg/m2

• at 6 months if HBA1C >/= 57mmol/mol

• Combination
◦ metformin + sulfonylurea + glitazones
◦ Metformin + gliptins ( DPP4 inhibitors)
◦ Metformin + SGLT-2-i
◦ Metformin + incretin analogs( GLP- 1) + sulfonylurea
◦ Insulin + metformin

Complications of diabetes mellitus

• acute and chronic complications

Acute complications
• hypoglycemia
• Lactic acidosis
• Diabetic keotacidosis
• Hyperosmolar hyperglycemic state
• Infections such as carbuncle, cellulitis, abscess, osteomyelitis

Chronic complications
• divided into microvascular and macrovascular

Microvascular / micro angiopathy

Opthalmopathy
• diabetic retinopathy
• Cataracts
• Rubeosis iridis ( formation of new vessels on the iris) - leads to glaucoma
• Mononeuritis multiplex ( CN III and VI palsies )

Nephropathy
• evidenced by microalbuminuria (negative urine dipstick with a urine albumin
creatinine level ( UACR) >/= 3 mg/mol

Neuropathy
• has sensory, motor and autonomic manifestation

• sensory : symmetric sensory polyneuropathy. Rx: pregabalin, paracetamol, etc

• motor : diabetic amyotrophy, ( atrophy of the quadriceps, and pelvic femoral

muscles)

• Autonomic : gastatory sweating, postural hypertension , erectile dysfunction /

impotence, gastroparesis, urine retention, diarrhea

Macrovascular
• coronary artery disease
• Cerebrovascular disease
• peripheral vascular disease
• Diabetic foot

Diabetic ketoacidosis
• Results from a persistence in hyperglycemia.
• majorly seen in type 1 but less common in type 2.

• characterised by a triad of: hyperglycemia, ketonemia and ketouria

diagnosis :
◦ increase in serum level of ketones >/= 5mmol/l. ( ie ketonemia)
◦ increase in the blood glucose, >/= 13.8 mmol/l
◦ Loss of bicarbonates such that, serum bicarbonates < 18mmol/l
◦ pH < 7.3 with an increased anion gap
Pathophysiology
• due to the increased level of glucose and near/absolute deficiency of insulin, the
cells are unable to uptake and utilize the glucose
• This results in an increased break down of substrates for gluconeogensis such as
fat and proteins. Ie lipolysis and proteolysis
• The fat is broken down into fatty acid and glycerol
• This results in an increased beta oxidation of the fatty acids
• Due to the hyperglycemia, there in an increased level of acetyl co enzyme-A
• this results in the inhibition of the enzyme, pyruvate dehydrogenase and
activation of pyruvate carboxylase, leading to the disposition of oxaloacetate
from the kerbs cycle ( tricarboxylic acid cycle)m ie prevents it from entering the
cycle and hence is used to produce energy
• Oxaloacetate is further inhibited by the high level of NADH ( reduced nicotinamide
adenine dinucleotide )
• The acetyl co enzyme A are then converted into the ketone bodies

Severity of dka
• severity can be assessed based on various factors including the HCO3- level and pH
Mild - HCO3 : 18-15 mmol/l , pH : 7.3 - 7.25
Moderate - HCO3 : 15-5 mmol/l , pH : 7.24- 7
Severe dka : < 10 mmol/l , ph < 7

Ketone bodies
Acetone - true ketone ( account for the fruity smell of the breath)
Acetoacetic acid / acetoacetate - true acid ( account for the acidosis )
Betahydroxybutyruc acid / beta hydroxybutyrate - hydroxy acid ( high levels
account for nausea and vomiting)

Types of Insulin and their peak types

rapid acting insulin : for meals eaten at the same time as injection
• insulin lispro : 30-90min
• insulin aspart : 60-90 mins
Short acting insulin : for meals eaten within 30-60 mins
• regular : 2-5 hours

Intermediate acting : insulin needs for about half a day or overnight

• NPH or isophane insulin : 4-12 hours

Long acting : insulin needs for the whole day

• Insulin glargine : no peak time ( since insulin is delivered at a steady rate )
• insulin detemir: 6-8 hours

Pre mixed : combination of intermediate and short acting insulin

• taken 2 or 3 times a da before mealtime
• humulin 70/30 : 2-4 hours
• Novolin 70/30 : 2-12 hours

Clinical features of DKA

• nausea and vomiting
• Abdominal pain
• Kussmaul respiration ( deep and labored breathing with the objective of expelling
CO2)
• Fruity breathe smell
• altered consciousness ( confusion, coma)
• Dehydration ( due to the osmotic diuresis & nausea and vomiting)
• general body weakness
• Prostration
• Polyuria
• Weight loss
• Fever ( if triggered by infection )
• Cough

Investigations
• FBC
• ABG
• Bue creatinine
• Serum bicarbonate concentration
• Urine dip stick ( ketones, glucosuria)
• Chest x ray
• ECG

Reason for hypokalemia

• due to the high levels of the ketones causing ketoacidosis, potassium is
exchanged with h+ going into the cell,
• And due to the persistent diuresis , potassium is excreted by the kidneys causing
hypokalemia.

Principles of management of DKA

• primary survey / initial assessment ( ABC)
• Fluid therapy
• Insulin therapy
• Correction of electrolyte and acid base imbalance
• Antibiotic cover

Fluid and insulin therapy ( Modified Albertis regimen )

• fluid and insulin therapy are done together but time of administration varies
eventually
• Insulin is given hourly and fluids are given per the times below
• Check RBS first and every hr before proceeding to the next step ( it will indicate
the dose of insulin to be given )
• The moment it falls below 13 mmol/l, give 500ml of 5% dextrose and switch to
the sliding scale for insulin therapy and stop IV fluids ( to prevents further drop
in glucose level , c=n/V)
• Switch back to albertis regimen if glucose levels rise to 18 mmol/l

Time for fluids Fluid therapy Insulin therapy

• 1st 30 mins • Give 1l of n/s 10iu stat ( 5iu IV + 5 iu
im)
• next 1 hour • 1l of n/s • 5IU sc insulin
• next 2 hours • 1l of n/s • 5iu sc insulin
• 5 iu sc insulin
• next 4 hours • 1l of n/s • 5iu sc insulin
Sliding scale
• this is done every 4 hours , ie check rbs 4 hourly and give corresponding amount
of insulin
RBS (mmol/l) • hence maximum
Fluid therapy number of doses
• 0-6 ( 5.9999) • no insulin
• 6-9 (8.9999) possible in a day
• 2 iu insulin sc is 6 doses
• 9-12 ( 11.9999) • 4 iu sc
• 12-15 (14.9999) • 6 iu
• 15-18 ( 17.9999) • 8 iu

• Done for a maximum of 2 days

• if rbs is greater or equal to 18 mmol/l m switch to modified albertis regimen
( MAR)

After the 2 days of sliding scale, calculate the average insulin requirement of the
patient based on the insulin given.

Example : 1st day, patient takes a total of 16 iu of insulin. Second day : 22 iu

Average dose will be 16+22/ 2 = 19iu ~20 iu

• of this 2/3 will be given in the morning( mane) , in this case ~ 14

• And 1/3 will be given in the evening( 1/3)

• check response with RBS ( morning dose ), FBS ( evening dose) and if any are high
or low, adjust the dose

Electrolyte therapy
• correction of potassium levels

• mild hypokalemia -oral potassium tablets ( slow K)

• Severe : potassium chloride

Acid base imbalance : sodium bicarbonate

Antibiotic cover
• broad spectrum antibiotics

HHS Vs DKA
• Management is the same except there is no acid base correction in dka

HHS dka
Common in type 2 common type 1
Little to no Ketonuria ketones are present
pH >7.3 ph < 7.3
Glucose > 33.3mmol/l glucose > 13.8 mmol/l
no fruity breath fruity breath odor
HCO3 is normal HCO3 less than 18
No kussmaul respiration Kussmaul respiration
Anion gap is normal increased anion gap
Plasma osmolality > 290 mOsmol/l Plasma osmolality > 320 mOsmol/l

Anion gap
• the difference between the concentrations of cations and anions in the blood

Anion gap = cations - anions

= NA+ - (Cl + HCO3 ) = 12+/- 2, ie 10-14

= (na+k ) + ( Cl + HCO3 ) = 12+/- 4 mmol/l , ie 8-16 mmol/l

Plasma osmolarity
Plasma osmolality = 2Na + glucose + urea
18 2.5

Normal po = 280 - 295 mmol/l

Diabetic retinopathy
• it is the oThological breakdown of the retina vasculature due to persistent
hyperglycemia emia as encountered in patients with usually poorly controlled DM.

• Excess Glucose is toxic to the endothelium of the blood vessels

• Also glucose in excess, can undergo a reaction to form sorbitol , which is also
harmful to the mircrovasculature of the central retinal artery resulting in the
deposition of hyaline and compromised perfusion through the vessel

Stages of diabetic retinopathy

stage 1 - background retinopathy

microangiopathy ( dots)
Haemorrhage ( blots)
Hard exudates ( lipid deposit )

Treatment for stage 1 :refer to ophthalmologist and intravitreal triamcinolone

Stage 2 - preproliferative retinopathy

• cotton wool spot ( microinfarcts)
• Haemorrhage
• Venous beading

Treatment
• refer to the ophthalmology

Stage 3 - proliferative retinopathy

• neoangiogeneiss : new vessels are formed

Treatment : laser photocoagulation

Stage 4- maculopathy
• decreased visual acuity
• Retinal detachment

Treatment
• laser photcoagulation

Diabetic foot
meggit Wagner classfication of diabetic foot
Grade 0 - pre/ post ulcerative lesions fully epithelialised / no open lesions / ulcer
Grade 1 - superficial ulcers, limited to the dermis( can be full thickness )
Grade 2 - deep ulcers , extending to the joint and tendons without formation of
abscesses and osteomyelitis
Grade 3 - deep ulcers with the formation of abscesses, osteomyelitis and joint
sepsis
Grade 4 - gangrene involving the forefoot, or the heel
Grade 5 - gangrene involving the whole foot

Advice
• don’t walk barefooted
• Don’t bite nails or use blades, preferrably use a nail cutter