DIABETES MELLITUS

SUPERVISOR: DR SHALEENA
Type 2 DM
Asraf Helmy Bin Zainal Kadri
• Type 2 Diabetes Mellitus (T2DM) is a prevalent non-communicable disease
(NCD)
• T2DM is primarily due to insulin resistance as well as deficiency. The insulin
resistance state results in increased hepatic glucose output, reduced
utilisation of glucose by various organs, increased renal reabsorption of
glucose and reduced incretin hormones production among others.
• In general T2DM is an important risk factor for cardiovascular disease and
results in various other complications namely nephropathy, retinopathy,
neuropathy and dermatopathy.
• Currently there is no known cure but the disease can be controlled
enabling the individual to have an improved quality of life.
• The main aim of management is directed at reducing acute and chronic
complications (microvascular and macrovascular).
SCREENING AND DIAGNOSIS
• 2.1 Objective
• To detect pre-diabetes and diabetes among the general as well as
high-risk populations, whilst ensuring timely appropriate intervention.
• 2.2 Strategy
• Screening the general population for at risk individuals.
• Screening of specific high-risk population e.g. those with history of
gestational diabetes mellitus.
• 2.3 Who Should Be Screened
• 2.3.1 Symptomatic individuals
• • Any individual who has symptoms suggestive of diabetes (tiredness,
lethargy, polyuria, polydipsia, polyphagia, weight loss) must be
screened.
• 2.3.2 Asymptomatic individuals (Screening should be done annually)
• Testing should be considered in all adults who are overweight or obese (BMI 􀀁 23 kg/m2 or
have a waist circumference ≥80 cm for women and ≥ 90 cm for men), and have one or more
of the following additional risk factors for diabetes:
• First-degree relative with diabetes
• History of cardiovascular disease (CVD)
• Hypertension (BP ≥ 140/90 mm Hg or on therapy for hypertension)
• Impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) on previous testing
• High density lipoprotein (HDL) cholesterol <0.9 mmol/L or triglycerides (TG) >2.8 mmol/L
• Women who delivered a baby weighing ≥ 4 kg or were diagnosed with gestational diabetes
mellitus (GDM)
• Physical inactivity

• In those without these risk factors, testing should begin at the age of 30 years. If
tests are normal, screening should be done annually
• 2.4 Screening Test
• Screening can be done by measuring
either venous or capillary blood using
glucometer. Tests that can be
performed are A1c, oral glucose
tolerance test (OGTT), fasting blood
glucose or random blood glucose.
• Using A1c as a Screening Test for Diabetes
• A1c is formed by a non-enzymatic glycation of haemoglobin. It
reflects the average blood glucose level over the past 3 months.
• Although OGTT is the "gold standard" for diagnosing diabetes, it is
known to be poorly reproducible and is cumbersome to perform.
• Using A1c level to diagnose diabetes is convenient since
therapeutic decisions are also based on this value, regardless of the
findings of the OGTT.
• A1c is not appropriate for diagnosis of diabetes in:
• 1. Adolescents (<18 years old) since the diagnostic cut-off point was
derived in those >18 years.
• 2. Patients taking medication that may cause rapid glucose rise e.g.
steroids, antipsychotics.
• 3. Patients taking iron supplements (may falsely lower A1c levels).
• 4. Patients with acute pancreatic damage, including pancreatic surgery.
• 5. Patients in chronic kidney disease (CKD) stage 4 or 5 and those on
erythropoietin injections.
• 6. Anaemia due to iron, B12 or erythropoietin deficiencies.
• 2.6 Diagnosis
• Diagnosis must be confirmed by measurement of venous plasma
glucose or A1c level. Venous sample
• for plasma glucose and A1c should be taken prior to initiating therapy.
TYPE 1 DM
INTRODUCTION
• DM is a group of metabolic disorders characterized by hyperglycemia
and abnormalities in carbohydrate, fat and protein metabolism
Pathophysiology
• TIDM is primarily due to pancreatic islet β-cell destruction leading to
severe insulin deficiency
• manifested by low or undetectable plasma concentration of C-peptide
• Strong familial genetic link
MARKERS
• glutamic acid decarboxylase (GAD) antibody,
• insulin autoantibodies (IAA),
• anti-islet antibody (ICA),
• Protein thyrosine phosphatase antibody (ICA512 or IA2A)
• zinc transporter 8 (ZnT8)
Risk factors
• genetics: the most susceptible haplotypes are the DRB1*0301-
DQA1*0501-DQB1*0201 and the DRB1*0405-DQA1*0301-
DQB1*0302, DRB1*0401-DQA1*0301-DQB*0302, and DRB1*0402-
DQA1*0301-DQB1*0302
• high birth weight (>4 kg)
• early introduction of cow’s milk before three months of age
• rapid growth within first two years of life
• enterovirus infection
• high energy food intake especially disaccharides and sucrose
• Classically, T1DM children and adolescents present with history of
polyuria, polydipsia and weight loss over 2 - 6 weeks.
• Some of them can have rapid onset of symptoms within days and
present in diabetic ketoacidosis (DKA), while others can have a slower
onset of symptoms over several months.
Non-emergency presentation
• Recent onset of enuresis in previously toilet-trained children
• Vaginal candidiasis especially in pre-pubertal girls
• Chronic weight loss or failure to gain weight in growing children
• Recurrent skin infections
Emergency presentation
• Moderate to severe dehydration
• Frequent vomiting
• Abdominal pain
• Continuing polyuria despite the presence of dehydration
• Weight loss due to fluid loss, and loss of muscle and fat
• Acetone-smelling breath
• Hyperventilation
• Decreased level of consciousness
• Hypotension
• Shock
Comorbidities
• Higher prevalence of autoimmune diseases
• Screening of thyroid function and measurement of antithyroid
peroxidase antibody should be done at diagnosis of type 1 diabetes
mellitus.
• If thyroid function is normal and antibody is absent, repeat screening
every two years.
• In patients with goitre or positive for thyroid antibody, repeat
screening more frequently
• Coeliac disease is mostly asymptomatic in patients with T1DM.
• The disease can only be detected in these patients by serologic
screening using anti-endomysium antibody and/or tissue
transglutaminase antibody, and confirmatory diagnosis using
intestinal biopsy.
• Screening for the disease should be done in suspected cases.
Diagnosis
• Diagnosis of diabetes can be made when:
• 1. classic symptoms and signs are present and
• fasting venous plasma glucose concentration is ≥7.0 mmol/L, and/or
• the random venous plasma glucose concentration ≥11.1 mmol/L
• Additional support for the diagnosis of T1DM include:
• i. low or undetectable C-peptide levels
• ii. presence of diabetes-associated autoantibodies
(GAD/IAA/ICA512/IA2/ZnT8)
Signs and symptoms
• Polyuria
• Polydipsea
• Polyphagia
• DKA
• Unexplained weight loss
 Diabetes Mellitus

Management Outline
Counselling.
Treatment.
Non-pharmacological
Pharmacological
Follow-up.
 Diabetes Mellitus

Counselling
Explain about the disease
Possible complications
Treatment available
Target of treatment
Compliance
 Diabetes Mellitus

Non-pharmacological treatment
Diet
Physical exercise
Weight Reduction
 Diabetes Mellitus

Non-pharmacological treatment
Diet
 60%...... Complex carbohydrates
 30%...... Fats and oils
2/3 mono- & polyunsaturated FA
 15%...... Protein
 Restrict salt intake to below 10 g/day
especially in HPT patients
 Diabetes Mellitus

Non-pharmacological treatment
Physical activity
 Aerobic exercises (e.g. brisk walking, cycling, jogging,
swimming) at least 30
minutes, 3 times per week.
 Avoid sedentary activities (e.g. watching TV, playing
computer games etc.)
 Healthy lifestyle habits should be preferred
(e.g. use stairs rather than the elevator, walk to nearby
shops instead of driving
etc.)
 Diabetes Mellitus
Pharmacological treatment
Biguanide
Sulfonylurea
Insulin secretagogues
Meglitinide
α-Glucosidase inhibitor
Thiazolidinedione (TZD)
Dipeptidyl peptidase-4 inhibitor
Incretin mimetics
Insulin
 Diabetes Mellitus
Available agents
Class Agents
Biguanide Metformin (Glucophage®)
Sulfonylurea Glibenclamide (Daonil®)
Gliclazide (Diamicron®)
Glimepiride (Amaryl®)
Meglitinide Repaglinide (NovoNorm®)
Nateglinide (Starlix®)
α-Glucosidase inhibitor Acarbose (Glucobay®)
Thiazolidinedione Rosiglitazone (Avandia®)
Dipeptidyl peptidase-4 (DPP-4) inhibitor Sitagliptin (Januvia®)
Vildagliptin (Galvus®)
Incretin mimetics Exenatide (Byetta®)
Insulin Short/Intermediate/Long acting
 Diabetes Mellitus

What are the mechanisms of action?

Augment Insulin Enhance Insulin Delay

Supply Action Carbohydrate
(Insulin (Insulin Absorption
Secretagogue) Sensitizer)
Sulfonylureas Biguanides α-Glucosidase
Meglitinides Thiazolidinediones inhibitor
 Diabetes Mellitus

Sites of action?
Acarbose
Rosiglitazone
– +

GI tract Plasma glucose Muscle/Fat

Carbohydrate Glucose
breakdown Glucose Uptake
production(PPAR Gamma + +
– linresistance) – Injected
Receptor-decrease Insu

Metformin Liver
insulin
Insulin
secretion –

Pancr+eas

Sulfonylureas
Metiglinide
 Diabetes Mellitus

Sites of action?
 Incretins Regulate Glucose Homeostasis
Through Effects on Islet Cell Function
Ingestion of
food Glucose dependent
 Insulin Insulin increases
from beta cells peripheral
(GLP-1 and GIP) glucose uptake

GI tract Release of Pancreas

incretin gut
hormones Beta cells Blood glucose
Alpha cells control
Active GLP-1
and GIP
Increased insulin and
decreased glucagon
t Glucagon reduce
from alpha cells (GLP- hepatic
1) glucose output
Glucose dependent

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep
2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
 Diabetes Mellitus
Insulin?
 Diabetes Mellitus
Insulin?
 Diabetes Mellitus
Long-acting insulin?
 Diabetes Mellitus

Treatment strategy?
OHA Monotherapy
OHA Combination therapy
OHA + Insulin therapy
Insulin therapy
 Diabetes Mellitus

OHA + insulin combination therapy

Insulin sensitizer + insulin
Insulin sensitizer + insulin secretagogue
+ insulin
 Diabetes Mellitus

How do you follow this patient up?

Assessment of the disease
Assessment of complications
Assessment of compliance
Assessment of medications side effects
 Diabetes Mellitus

How do you follow this patient up?

History
Physical examination
Investigations
 Diabetes Mellitus

How do you follow this patient up?

History
 Symptoms of hypoglycaemia or hyperglycaemia
 Any evidence of infection
 Symptoms of complications
 Ensure compliance (drugs, diet, exercise)
 Symptoms of medications side effects
 Diabetes Mellitus

How do you follow this patient up?

Physical examination
 Blood pressure
 Waist circumference / BMI
 Foot examination
 Fundoscopy
 Diabetes Mellitus

How do you follow this patient up?

Investigations
 Urine (albumin, microalbuminuria, sugar)
 Fasting blood glucose
 HbA1c
 Fasting lipid profile
 Renal function test
HYPERGLYCEMIC HYPEROSMOLAR STATE
(HHS)
 Introduction
• HHS is characterized by severe hyperglycemia ( >30mmol/L) and hyperosmolality
(>320 mOsmol/kg )
• Diagnosis of hyperglycaemic hyperosmolar state (HHS) must be prompt and
managed intensively in high-dependency units or equivalent level of care.
• The elderly with multiple comorbidities are prone to HHS. However, with the
epidemiological shift of T2DM to the younger age group, HHS is often the initial
presentation in the younger age group.
• It has a higher mortality than DKA and vascular complications such as myocardial
infarction, stroke or peripheral arterial thrombosis are common. Well-described
complications such as seizures, cerebral oedema and osmotic demyelination
syndrome are uncommon.
• Rapid changes in osmolality during treatment may also be the precipitant of osmotic
demyelination syndrome.
• Whilst the presentation of DKA is rapid (within hours), HHS progresses over many
days. As a result, the dehydration and metabolic disturbances are more extreme.
• In HHS there is enough insulin to prevent lipolysis and ketogenesis but not adequate
for glucose utilization.
 Diagnostic Criteria of HHS

• Hypovolaemia
• Marked hyperglycaemia (BG >30 mmol/L)
• Osmolality >320 mosmol/kg
(Serum Osmolality =2(Na+ + K+) + Glucose + Urea)
 Important Clinical Features
• There is no significant hyperketonaemia (<3.0 mmol/L) or acidosis (pH >7.3,
bicarbonate >15mmol/L).
• The presence of acute cognitive impairment may be associated with:
1. cerebral oedema in severe cases
2. presence of significant electrolyte disturbances
3. hyperosmolality (>330 mOsmol/kg)
4.sudden drop in osmolality
5. severe dehydration
6. infection and sepsis
7. hypoglycaemia during treatment
8. renal failure
 Precipitating factors
• Precipitating factors for HHS are:
a) Infections and sepsis
b) Thrombotic stroke
c) Intracranial haemorrhage
d) Silent myocardial infarction
e) Pulmonary embolism
 Management goals
The goals of treatment of HHS are to treat the underlying cause as well as
to gradually and safely:

• Normalise the osmolality

• Replace fluid and electrolyte losses
• Normalise blood glucose
• Prevention of complications
 Principles of treatment
• Intravenous (IV) 0.9% saline solution is the principle fluid to restore circulating volume and
reverse dehydration. Intravenous 0.45% saline solution is only recommended if the osmolality
is not declining despite adequate positive fluid balance.
• Monitor serum osmolality regularly to prevent harmful rapid changes in osmolality.
• The rate of rehydration will be determined by assessing the combination of initial severity
and any pre-existing comorbidities. Rapid rehydration may precipitate heart failure but
insufficient rehydration may fail to reverse acute kidney injury.
• An initial rise in sodium is expected and is not in itself an indication for hypotonic fluids.
Thereafter, the rate of fall of plasma sodium should not exceed 10 mmol/L in 24 hours.
• The fall in blood glucose should be no more than 5 mmol/L/hr.
• Low dose IV insulin (0.05 units/kg/hr) should be commenced once blood glucose is
no longer falling with IV fluids alone or immediately if there is significant ketonaemia
• Prophylactic low molecular weight heparin (LMWH) is recommended unless
contraindicated.
• Hyperkalaemia, hypokalaemia, hypophosphataemia and hypomagnesaemia are
common and should be corrected accordingly.
• In acutely ill patients, pyrexia may not be present. If sepsis is highly suspicious, the
source of infection should be sought and treated.
• Discharge planning includes diabetes education, dietitian referral, education on
medication and insulin administration (if patient is on insulin) to reduce the risk of
recurrence and prevent long-term complications.
HYPOGLYCEMIA
What is it?
• Low plasma glucose levels (<4mmol/L)
• Development of autonomic or neuroglycopenic symptoms in patients
taking insulin or OHA which are reversed by caloric intake
Common causes of hypoglycemia
• When a person with diabetes had taken too much insulin
• Exercising without proper meal intakes
• Skipping meals frequently
• Lack of glucagon on body
• Excessive alcohol consumption
• Insulinoma
• Certain common risk factors
 Treatment
• Mild to moderate : ingestion of simple carbohydrates ( 1 tablespoon
of honey, ¾ cup of juice, 3 teaspoon of table sugar) then repeat DXT
after 15 mins. If DXT is still less than 4mmol/L, take another 15g of
simple carbohydrates
• Severe ( conscious patient ) : patient to take 20g of simple
carbohydrates and repeat the above steps
• Severe ( unconscious patient) : to give IV D50% 20-50cc over 1-3 mins
and repeat DXT in 30 mins. If this happens outside the hospital
setting, give a tablespoon of honey to the person.
Hypoglycaemia unawareness
• Hypoglycaemia unawareness occurs when the ability to perceive the
onset of hypoglycaemia is either diminished or completely lost at the
physiological plasma glucose concentration at which warning
symptoms normally occur. Repeated hypoglycaemia blunts
symptomatic and hormonal responses to subsequent episodes
leading to hypoglycaemia unawareness.
• Hypoglycaemia unawareness increases the incidence of severe
hypoglycaemia by 17-fold for T2DM patients.
DIABETIC KETOACIDOSIS
• Most serious acute complications.
• High mortality rate if unrecognised. The overall mortality is <1%, mortality rate
>5% in the elderly.
• Precipitating factors: infection, missed therapy, acute coronary syndrome, CVA,
surgery etc.
1. Diagnostic criteria: (All three must be met)
2. Capillary blood glucose >11 mmol/L
3. Capillary ketones >3 mmol/L or urine ketones ≥2+
4. Venous pH <7.3 and/or bicarbonate <15 mmol/L
High Dependency Unit Care
• High-dependency unit (HDU)admission and insertion of central line in
the following circumstances:
• Elderly
• Pregnant ladies
• Heart or kidney failure
• Other serious comorbidities
• Severe DKA
Criteria For Severe Ketoacidosis
• i. Venous bicarbonate <5 mmol/L
• ii. Blood ketones >6 mmol/L
• iii. Venous pH <7.1
• iv. Hypokalaemia on admission (<3.5 mmol/L)
• v. Glasgow Coma Scale (GCS) <12
• vi. Oxygen saturation <92% on air (arterial blood gases required)
• vii. Systolic BP <90 mm Hg
• viii. Pulse >100 or <60 beats/minute
• ix. Anion gap >16 [Anion Gap = (Na+ + K+) – (Cl- + HCO3-)]
 Principles of management
•
 What is the next step of management?
• Expectation: Patient should be eating and drinking and back on normal
insulin
• If DKA is not resolved identify and treat the reasons for failure to respond
• Convert to subcutaneous regime when biochemically stable (blood ketones
<0.3 mmol/L, pH >7.3) and the patient is ready and able to eat.
• Do not discontinue intravenous insulin infusion until 30 minutes after
subcutaneous short acting insulin has been given.
What is the next step of management?
• Calculating subcutaneous insulin dose in insulin-naïve patients;
Calculating a Basal Bolus (QID) Regimen.
• Estimate Total Daily Dose (TDD) of Insulin :
• The TDD can be calculated by multiplying the patient’s weight (in kg)
by 0.5 to 0.75 units.
• Use 0.75 units/kg for those thought to be more insulin resistant e.g.
obese, acanthosis nigricans
Example
• An 80-kg person would require approximately 80 x 0.5 units or 40
units in 24 hours
• Give 50% of total dose at bedtime in the form of long acting insulin
and divide remaining dose equally between pre-breakfast, pre-lunch
and pre-evening meal.
• E.g. Short-acting insulin 7u tds & 20u on