Carmel Christy Christopher MM20605 MD Student

L14: Diabetes Mellitus P1

• Definition of diabetes mellitus

o A group of metabolic disorders sharing common feature of hyperglycaemia due to absolute or
relative deficiency of insulin.
o Result from inadequate secretion of insulin or target tissue resistance to its action.
o DM can lead to vascular changes and neuropathy affecting number of organs
• Classification of Diabetes Mellitus (Aetiological classification)

• Cause by β cell destruction, leads to absolute insulin deficiency

• Immune-mediated
Type 1 diabetes
• Idiopathic
• Dr mentioned: Chlidhood onset
• Cause by insulin resistance with relative insulin deficiency
Type 2 Diabetes
• Dr mentioned: Adult onset
• Maturity-Onset Diabetes of the Young (MODY), caused by mutation
in;
• MODY1: Hepatocyte nuclear factor 4alpha [HNF-4a]
• MODY2: Glucokinase
Genetic defects of β-cell • MODY3: Hepatocyte nuclear factor 1 alpha [HNF-1a]
function
• MODY4: Insulin Promoter factor [IPF-1]
• MODY5: Hepatocyte nuclear factor 1β [HNF-1β]
• MODY6: Neurogenic differentiation factor 1 [Neuro D1]
• Mitochondrial DNA mutations

Genetic defects in • Defects in proinsulin conversion

insulin processing or • Insulin gene mutations
insulin action • Insulin receptor mutations
• Chronic pancreatitis
• Pancreatectomy
Exocrine pancreatic • Neoplasia
defects • Cystic fibrosis
• Hemachromatosis
• Fibrocalculous pancreatopathy
• Acromegaly
• Cushing Syndrome
Endocrinopathies • Hyperthyroidism
• Pheochromocytoma
• Glucagonoma
• Cytomegalovirus
Infections
• Coxsackie virus B
• Glucocorticoids, Thyroid hormone, Alpa-interferon, Protease
Drugs inhibitors, Beta-adrenergic agonist, Thiazides, Nicotinic acid,
Phenytoin

Genetic syndromes • Down syndrome

associated with • Kleinfelter syndrome
diabetes • Turner syndrome
Gestational Diabetes • In pregnant women
Carmel Christy Christopher MM20605 MD Student

• Type 1 Diabetes Mellitus

o Definition
▪ Autoimmune disease which characterized by pancreatic β cell destruction and absolute
deficiency of insulin
o Pathogenesis
▪ Autoimmune reaction
• Caused primarily by immune effector cells reacting against endogenous against
endogenous β-cell antigens
• T lymphocytes (CD4+, CD8+) reacting against islet autoantigens:
o Insulin, β-cell enzyme Glutamic acid decarboxylase & islet cell auto
antigen 512 (ICA 512). Islets show cellular necrosis and lymphocyte
infiltration (insulitis)
▪ Genetic susceptibility
• (50% genetic susceptibility) Class II MHC locus, chromosome 6p21 (HLA-D)
• (95% of Type 1 diabetes) HLA-DR3, HLA-DR4 haplotype or both
• Non-MHC genes
o Insulin gene with VNTRs (variable number of tandem repeats) in
promoter region
• Polymorphism in CTLA4 and PTPN22
▪ Environmental factors
• Viral infection
o In the pancreas alters β cells’ immunogenicity
o Example of viruses
▪ Coxsackie B4, Retroviruses, Rubella (in utero), Cytomegalovirus, &
Epstein-Barr virus
• Stress
o Stimulate the secretion of counter-regulatory hormones and possibly by
modulating immune activity
• Dietary factors
o Various nitrosamine (smoked and cured meat) and coffee → diabetogenic
o Bovine serum albumin (major constituent of cow’s milk) → diabetogenic
(Pathogeneses of type 1 diabetes
– sequence of events)
Carmel Christy Christopher MM20605 MD Student

• Type 2 Diabetes Mellitus

o Caused by a combination of peripheral resistance to insulin action and an inadequate secretory
response by the pancreatic-β-cells (“relative insulin deficiency”).
o Pathogenesis
▪ Genetic Factors
• Genetic susceptibility
o 90% risk rate in monozygotic twins
o First-degree relatives have 5-to 10-fold higher risk of developing type 2
diabetes than those without a family history.
• Polymorphisms in genes associated with insulin secretion
▪ Environmental Factors
• Obesity, particularly central or visceral obesity
• Sedentary lifestyle
• Modest weight loss through dietary modifications can reduce insulin resistance
and improve glucose tolerance.
▪ Metabolic Defects in Diabetes
• Insulin resistance
o Decrease response of peripheral tissues to insulin, Failure of target tissues
to respond normally to insulin (liver, skeletal muscle, and adipose tissue)
o Insulin resistance results in
▪ Failure to inhibit endogenous glucose production
(gluconeogenesis) in the liver, which contributes to high fasting
blood glucose levels
▪ Failure of glucose uptake and glycogen synthesis to occur in
skeletal muscle following a meal, which contributes to high post-
prandial blood glucose level
▪ Failure to inhibit lipoprotein lipase in adipose tissue, leading to
excess circulating free fatty acids (FFAs), which in turn, amplify
the state of insulin resistance
o Obesity and insulin resistance
▪ It is an important factor contribute to insulin resistance
• Risk of diabetes increases as BMI increases
• Central obesity (abdominal fat) more likely to be linked
with insulin resistance than peripheral
(gluteal/subcutaneous) fat depots
▪ Factors that linked obesity and insulin resistance (Obesity-
associated Factors)
Carmel Christy Christopher MM20605 MD Student

Development of Type 2 Diabetes mellitus • Circulating non-esterified fatty acids (NEFA)

o Intracellular triglyceride (TG) & products of free
fatty acids (FFA) cause potent inhibitors of
signalling pathway
• Inflammatory mediators (proinflammatory cytokines)
o Adipose tissue also secretes a variety of pro-
inflammatory cytokines like tumour necrosis factor,
interleukin-6, and macrophage chemo attractant
protein – These cytokines induce insulin resistance
by increasing cellular “stress”.
• Adipokines (adipose cytokines)
o Both pro-hyperglycemicadipokines (e.g., resistin,
retinol binding protein 4 [RBP4]) and anti-
hyperglycemicadipokines (leptin, adiponectin)
• β-cell dysfunction (Inadequate Insulin secretion)
o Failure of compensation by β-cells
▪ Inability of β-cells to adapt themselves to the long-term demand
of peripheral tissue, insulin resistance and increased insulin
secretion.
Amyloid deposition in islet o Several mechanisms have been implicated in promoting β-cell dysfunction
in type 2 diabetes including
▪ Lipo-toxicity (high circulating FFA)
▪ Glucotoxicity (chronic hyperglycaemia).
▪ An abnormal “incretin effect,” leading to reduced secretion of GIP
and GLP-1, hormones that promote insulin release.
▪ Amyloid deposition within islets (unclear cause or effect)
▪ Genetics (genes that control insulin secretion)
• Symptoms of Hyperglycaemia
o Polyuria/Nocturia
o Polydipsia (intense thirst & dry mouth)
o Hyperphagiaor polyphagia (excessive hunger or increased appetite)
o Weight loss/muscle weakness/fatigue, tiredness
o Pruritusvulvae, balanitis
o Headache, nausea
o Blurring of vision
o Mood change, irritability, difficulty in concentrating, apathy pathophysiology of symptoms in DM
• Pathophysiology of symptoms in DM
Carmel Christy Christopher MM20605 MD Student

o Hyperglycaemia induces glycosuria resulting osmotic dieresis and polyuria.

o Renal water loss combined with hyperosmolarity tends to deplete intracellular water triggering
the osmoreceptors of thirst centres of the brain producing polydipsia (intense thirst)
o The catabolism of proteins and fats tends to induce a negative energy balance leads to
increasing appetite (polyphagia)
o Despite the increased appetite, catabolic effects prevail, resulting in weight loss and muscle
weakness.
o Diabetics are plaqued by enhanced susceptibility infection of skin & mucocutaneous areas lead
to candidiasis of vulva producing pruritus vulvae (genital candidiasis)
• Classic Triad of Diabetes
o Onset of TYPE 1 DIABETES usually marked by the triad polyuria, polydipsia, polyphagia
▪ Polyuria: Hyperglycaemia exceeds the renal threshold for reabsorption, and glycosuria
ensues. The glycosuria induces an osmotic diuresis and thus polyuria, causing profound
loss of water and electrolytes.
▪ Polydipsia: The obligatory renal water loss combined with the hyperosmolarity resulting
from the increased levels of glucose in the blood tends to deplete intracellular water,
which triggers the osmoreceptors of the thirst centres of the brain. Then, intense thirst
(polydipsia) appears.
▪ Polyphagia: The catabolism of proteins and fats tends to induce a negative energy
balance, which in turn leads to increasing appetite (polyphagia)
• Metabolic Syndrome: Insulin Resistance Syndrome
o Called as Reaven’s syndrome and Syndrom X.
o Features of metabolic syndromes
▪ Hyperinsulinemia
▪ Type 2 DM or Impaired Glucose Tolerance
▪ Hypertension
▪ Low HDL cholesterol; elevated triglycerides
▪ Central (visceral) obesity
▪ Microalbuminuria
▪ Increased fibrinogen
▪ Increased plasminogen activator Inhibitor-1
▪ Increased C reactive protein (CRP)
▪ Elevated plasma uric acid
▪ Increased sympathetic neural activity
• Investigation
o Urine Testing
▪ Glucose
Carmel Christy Christopher MM20605 MD Student

• Using sensitive glucose-specific dip stick (best: urine passed 1-2hrs after meal)
• If glycosuria detected → further assessment by blood test
• Disadvantage of glucose urine testing
o Low renal threshold (Pregnancy & young)
o Rapid rise of glucose after meal + glycosuria
▪ Ketones
• Identified by nitroprusside reaction
• Normally present after fasting, strenuous exercise, vomiting
• Associated with glycosuria—DM is highly likely.
▪ Protein
• Dipstick testing → standard procedure
• Identify presence of renal disease or UTI in Diabetes Mellitus patient
• Detect urine albumin >300mg/l
• Small amount of urinary albumin (Microalbuminuria)
• Provides indicator for the risk of developing diabetic nephropathy and/or
macrovascular disease.
o Blood testing
▪ Glucose
• Normal blood glucose → 70-120mg/dl or 3.8-6.6 mmol/L
• Using enzymatic (glucose oxidase reaction → cheap, reliable & automated)
• Measured with colorimetric or other testing sticks, read with portable electronic
meter
• Three criteria for diagnosis of Diabetes mellitus:
o A random glucose >200mg /dl (11.1 mmol/L) with classical signs and
symptoms
o A fasting glucose >126mg/dl (7.0mmol/L) on more than one occasion
o An abnormal oral glucose tolerance test (OGTT) in which the glucose is
>200mg/dl (11.1mmol/L) 2 hours after carbohydrate load.
▪ Glycated haemoglobin
• Accurate and objective measure
• Used as assessment of glycaemic control in diabetes mellitus
• In DM → the slow non-enzymatic covalent attachment of glucose to haemoglobin
(Glycation) increases the amount in the Hb A1 (Hb A1c) fraction relative to non-
glycated adult haemoglobin (Hb A0)
• Rate formation of Hb A1c is directly proportional to blood glucose concentration
• Difficult to interpret in patient with anaemia, during pregnancy, uraemia,
hemoglobinopathies
Carmel Christy Christopher MM20605 MD Student

▪ Blood lipids
• The concentration of serum lipids
o Total cholesterol
o Low Density Lipoprotein (LDL)
o High Density Lipoprotein (HDL)
o Triglyceride
• Blood is taken in fasting state
o Diagnostic criteria for DM according to the ADA & WHO
▪ A fasting plasma glucose ≥ 126 mg/dL (7.0mmol/L)
▪ A random plasma glucose ≥ 200 mg/dL (11.1mmol/L)
▪ 2-hour plasma glucose ≥ 200mg/dL during an oral glucose tolerance test (OGTT) with a
loading dose of 75gm, and
▪ A glycated haemoglobin (HbA1C) level ≥ 6.5%
▪ Euglycemia (Normal concentration of glucose in blood)
• Fasting <110mg/dl (6.1mmol/L)
• 2 hrs after glucose load <140mg/dl (7.7 mmol/L)
o Impaired glucose tolerance (pre-diabetes) definition
▪ A fasting plasma glucose between 100 and 125 mg/dL (6.1.and 7.0 mmol/L) (“impaired
fasting glucose”),
▪ Two -hour plasma glucose between 140 and 199 mg/dL (7.8 and 11.0 mmol/L) following
a 75-gm glucose OGTT, and/or
▪ A glycated haemoglobin (HbA1C) level between 5.7% and 6.4%
o Impaired Glucose Tolerance Test is indications for Oral Glucose tolerance Test (OGTT)