diabetes-mellitus.pdfgyguyuyiukhijhfjyfuygiug

Truth

1. Diabetes mellitus
By Dr. Haitham Nabeel
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2. Your Date Here Your Footer Here
The endocrine pancreas

3. Pancreatic Islets
Islets of Langerhans
•Millions of islets found in pancreatic tissue
•Endocrine portion of pancreas
•Beta cells: Insulin
•Most abundant cell type
•Centrally located
•Alpha cells: Glucagon
•Delta cells: Somatostatin
•Alpha/delta cells: Outer islet
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4. Insulin
•Protein hormone
•Synthesized by beta cells
•Synthesized as preproinsulin
•Made by ribosomes of rough endoplasmic reticulum
•Preproinsulin cleaved to proinsulin
•Transported to Golgi apparatus
•Packaged into secretory granules
•Proinsulin cleaved to insulin and C-peptide in granules
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5. Insulin
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6. Insulin Structure
•Alpha chain
•Beta chain
•Disulfide bridges
•C-peptide
•“Connecting” peptide
•Long half-life
•Indicator insulin production
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7. Clinical pearl!
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C-peptide
 is released by the β-cells in an
equimolar
 proportion to insulin but is not present
in
 exogenous insulin. It can, therefore, be used to
differentiate between endogenous
(e.g.,
 insulinoma, sulfonylurea use)
and
 exogenous hyperinsulinism.

8. Insulin Release
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9. Insulin
 release
•Insulin
 release stimulants 
•Glucose
 
•β
2
 
agonists
•Free
 fatty acids
•Amino acids
•Incretins
 
(e.g.,
 GLP-1 and GIP)
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10. Clinical pearl!
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Oral glucose results in a greater
increase in
 insulin levels than IV
administration.

11. Insulin secretion in
response to elevated
glucose
A-The incretin effect describes the
observation that insulin secretion is greater
when glucose is given by mouth than when
glucose is administered intravenously to
achieve the same rise in blood glucose
concentrations. The additional stimulus to
insulin secretion is mediated by release of
peptides from the gut and these actions are
exploited in incretin based therapies.
B-An acute first phase of insulin secretion
occurs in response to an elevated blood
glucose, followed by a sustained second
phase.
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12. Insulin
 release
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13. Insulin
 release
•Insulin
 release inhibitors 
•α
2agonists
•Epinephrine
•Cortisol
•Glucagon
•Somatostatin
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14. GLUT-2 Transporter
•Bidirectional glucose transporter
•Found in liver, kidney, beta cells
•Liver, kidney: Gluconeogenesis
•Beta cells: Glucose in/out based on plasma levels
•Also found in intestine, other tissues
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15. GLUT-4 Transporter
•Stored in vesicles in cells,
especially muscle
•Insulin → PIK3 pathway
→ GLUT-4 Activation
•Major mechanism for
increased glucose uptake
•Important muscle/fat
•Insulin exposure → GLUT-4 on surface
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16. Insulin Dependent Organs
•Muscle and fat
•Use GLUT-4 for glucose uptake
•Depend on insulin (no insulin = no GLUT-4)
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17. Insulin Independent Organs
• Brain and RBCs
•Use GLUT-1 for glucose uptake
•Not dependent on insulin
•Takes up glucose when available
•RBCs: No mitochondria (depend on glycolysis)
•Brain: No fatty acid metabolism (glucose/ketones)
•Liver, kidney, intestines
•Also insulin independent (GLUT-2)
•Other organs: nerves, lens
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18. Insulin Effects
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19. Insulin Effects
•↑ Glucose uptake (skeletal muscle, adipose tissue)
•↑Glycogen synthesis
•Inhibits gluconeogenesis
•↑ Fatty acid synthesis
•Activates acetyl-CoA carboxylase
•Inhibits hormone sensitive lipase
•↑ Protein synthesis
•Stimulates entry of amino acids into cells→protein synthesis
•Important for muscle growth
•Key side effect insulin therapy: weight gain
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20. Insulin Effects
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21. Insulin Effects
•Na+ retention
•Increases Na+ resorption in the nephron
•Lowers potassium
•Enhanced activity of Na-K-ATPase pump in skeletal muscle
•Insulin plus glucose used in treatment of hyperkalemia
•Inhibits glucagon release
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22. Glucagon
•Protein hormone
•Single polypeptide chain
•Synthesized by alpha cells
•Opposes actions of insulin
•Main stimulus release: low plasma glucose
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23. Glucagon
•Increases liver (not muscle) glycogen breakdown
•Raises blood glucose level
•Increases gluconeogenesis
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24. Glucagon effects
•Increases amino acid uptake in liver
•More carbon skeletons for glucose via gluconeogenesis
•Plasma amino acid levels fall
•Activates lipolysis via hormone sensitive lipase
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25. Glucagon receptor
•G-protein receptor
•Activates adenylyl cyclase
•Increases cAMP
•Activates protein kinase A
(PKA)
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26. Glucagon receptor
•Glucagon receptors mostly in liver
•Many activated processes occur in liver
•Breakdown of glycogen to raise plasma glucose
•Gluconeogenesis
•Most other tissues have lower density than liver
•Not found in skeletal muscle
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27. Hypoglycemia
•Unconscious patient with hypoglycemia
•Treatment:
•#1: IV dextrose
•#2: Intramuscular glucagon
•Useful when IV access cannot be established
•Raises plasma glucose level
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28. Beta Blocker Overdose
•Causes bradycardia and hypotension
•Drug of choice: Glucagon
•Activates adenylyl cyclase
•Different site from beta-adrenergic
agents
•Raises cAMP → ↑ myocyte calcium
•Same mechanism as beta stimulation
(via Gs proteins)
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29. Clinical pearl!
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Insulin and glucagon are tightly and reciprocally
regulated, such that the ratio of insulin to glucagon
in the portal vein is
a major determinant of hepatic glucose production
and other metabolic
processes, including lipolysis and ketogenesis

30. Blood glucose homeostasis
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31. Your Date Here Your Footer Here
Diabetes Mellitus

32. Diabetes Mellitus
•Diabetes mellitus is a clinical syndrome characterised
by an increase in plasma blood glucose
(hyperglycaemia).
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33. Overview
Typ
e 1
DM
Typ
e 2
DM
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34. Overview, pathophysiology
Autoimm
une
destructio
n of
 
β
cells
→
 absolut
e
 insulin
deficiency
Insulin
resistance,
progressiv
e
destructio
n
of
 pancrea
tic
 β-cells
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35. Overview, genetics
Positive
 HLA-
DR4
 and HLA
-
DR3
 associati
on
Weak
familial
predispositio
n
Negative
 
HLA
 asso
ciation
Strong
familial
predispo
sition
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36. Overview, onset
Childhood
onset
typically
 <
20
years
 but
can occur
at any age
Gradual
;
 usuall
y at
age
 >
40
years
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37. Overview, insulin
Very low
or absent
insulin
with high
insulin
sensitivit
y
Insulin
initially
elevated,
decreased
in
advanced
stage with
low insulin
sensitivity
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38. Overview, symptoms
Classic
symptom
s are
common
with high
risk of
DKA
Classic
symptoms
are
sometime
s absent
with low
risk of
DKA
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39. Overview, symptoms
Treated
with
insulin
and
only
insulin
Treated
with
lifestyle
changes,
oral
antidiabetic
drugs and
insulin
therapy
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40. Overview
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41. Epidemiology
•Type 1 DM
•Prevalence
•
∼
5–10% 
of all patients with diabetes
•Age
•Childhood onset typically
 < 20 years but can occur at any age
•Peaks at age
 
4–6 years 
and 
10–14 years
•Race: 
highest prevalence in non-Hispanic White
individuals
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42. Quick reference!
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More about the epidemiology
of type 1 DM is discussed in
pediatric endocrinology series.

43. Epidemiology
•Type 2 DM
•Prevalence
•415 million people had diabetes in 2015 (10% of the world adult
population)
•A pronounced rise in the prevalence of type 2 diabetes occurs in migrant
populations to industrialised countries
•Age
•Adult onset typically
 
> 40 years
•Mean age of onset is decreasing (it is is now seen in children and
adolescents)
•Gender: 
 >  ♂ ♀
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44. Medicine is diabetes!
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Diabetes is a major burden on health-care facilities
in all countries. Globally, in 2015, diabetes caused 5
million deaths in those aged 20–79 years, and
health-care expenditure attributed to diabetes was
estimated to be at least 673 billion US dollars,
or 12% of total health-care expenditure.

45. Classification according the WHO and ADA
•Type 1: formerly known as
 insulin-dependent (IDDM) or juvenile-
onset
 diabetes mellitus
•Autoimmune (type 1A)
 
•Idiopathic
 
(type 1B)
 
•LADA: 
Latent autoimmune diabetes in adults, a variant of diabetes
characterized by a late onset of
 type 1 (autoimmune) diabetes that is
often mistaken for
 type 2 diabetes.
•Type 2: formerly known as
 non-insulin-dependent (NIDDM)
or
 adult-onset diabetes mellitus
•Gestational diabetes
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46. Classification according the WHO and ADA
•Other types of diabetes mellitus
•MODY 
(maturity-onset diabetes of the young): genetic defects leading to β-cell dysfunction
•Different forms of
 autosomal dominant inherited diabetes mellitus that
manifest before the age of
 25
years
 and are not associated with obesity or autoantibodies.
•Pancreatogenic diabetes mellitus: following pancreatectomy
 and due to conditions that
lead to destruction of
 pancreatic endocrine islets (e.g., hemochromatosis, cystic fibrosis)
•Endocrinopathies:
 
Cushing disease,
 acromegaly
•Drug-induced
 diabetes,
e.g., due to
 
corticosteroids (steroid
 diabetes)
•Genetic defects affecting
 insulin synthesis
•Infections (e.g.,
 congenital rubella infection)
•Other genetic syndromes that are associated with diabetes mellitus (e.g.,
 Down syndrome)
•Rare immunological diseases: 
stiff person syndrome
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47. Your Date Here Your Footer Here
Diabetes mellitus: etiology
and pathogenesis

48. Multifactorial conditions!
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In both of the common types of diabetes,
environmental factors interact with
genetic susceptibility to determine which
people develop the clinical syndrome,
and the timing of its onset.

49. Etiology and pathophysiology
•Type 1 DM
•Autoimmune destruction of
 pancreatic 
β cells
 
(by T lymphocytes) in
genetically susceptible individuals
•HLA
 association: 
HLA-DR3 
and 
HLA-DR4
 
positive
 patients are at
increased risk of developing
 T1DM. 
•Associated with other autoimmune conditions
•Hashimoto thyroiditis
•Pernicious anaemia
•Celiac disease (strong association)
•Primary adrenal insufficiency
•Vitiligo
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50. Etiology and pathophysiology
•Type 1 DM
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51. Clinical pearl!
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Marked
hyperglycaemia, accompanied by the
classical symptoms of diabetes, occurs
only when 80–90% of the functional
capacity of β cells has been lost.

52. Etiology and pathophysiology
•Type 1 DM
•Genetic predisposition
•The risk is 1:300 in the general population
•The inheritance of type 1 diabetes is polygenic
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53. Etiology and pathophysiology
•Type 1 DM
•Environmental predisposition
•Wide geographical and seasonal variations in incidence
•Rapid acquisition of local disease incidence rates in migrants
from low- to high-incidence countries
•Through direct toxicity to β cells or by stimulating an
autoimmune reaction directed against β cells.
•Potential candidates fall into three main categories: viruses,
specific drugs or chemicals, and dietary constituents.
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54. Etiology and pathophysiology
•Type 1 DM
•Environmental predisposition
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Viruses
•Mumps
•Coxsackie B4
•Retroviruses
•Congenital
rubella
•CMV
•EBV
Chemicals
•Nitrosa
mines
•Coffee
Diet
•Bovine
serum
albumin
•Low levels
of vitamin D

55. Clinical pearl!
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It has also been proposed that reduced exposure to
microorganisms in early childhood limits maturation
of the immune system and increases susceptibility
to autoimmune disease (the ‘hygiene hypothesis’).

56. Etiology and pathophysiology
•Type 1 DM
•Autoantibodies to islet and/or β-cell antigens.
•Can be present long before the clinical presentation of type 1
diabetes
•Their detection can be useful in confirming a diagnosis of type
1 diabetes
•Typically present in 70–80% of newly diagnosed type 1 diabetes
•They are poorly predictive of disease progression and disappear
over time
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57. Clinical pearl!
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Autoantibodies can also be used to predict
disease with a 5-year risk of type 1 diabetes of
about 20–25% in people with a single positive
autoantibody, 50–60% in those with two
positive autoantibodies, and 70% in those
with three autoantibodies

58. Etiology and pathophysiology
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59. Etiology and pathophysiology
•Type 2 DM 
•Associated with
 
metabolic syndrome:
•A cluster of conditions thought to be caused by resistance to
insulin action and is much more common in individuals who
are obese.
•These include :
•Hypertension
•Dyslipidemia (↑LDL and TG with ↓ HDL)
•Non-alcoholic fatty liver disease
•Polycystic ovarian syndrome
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60. Clinical pearl!
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Intra-abdominal ‘central’ adipose
tissue is metabolically active and releases large
quantities of FFAs, which may induce insulin
resistance because they compete
with glucose as a fuel supply for oxidation in
peripheral tissues such as muscle.

61. Etiology and pathophysiology
•Type 2 DM
•Natural history
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62. Clinical pearl!
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The key feature in type 2 DM is a
‘relative’ insulin deficiency, such that there is
insufficient insulin production to overcome the
resistance to insulin action. This contrasts with type 1
diabetes, in which there is rapid loss of insulin
production, resulting in ketoacidosis and death if the
insulin is not replaced.

63. Etiology and pathophysiology
•Type 2 DM
•B-cell failure
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64. Etiology and pathophysiology
•Type 2 DM
•Genetic predisposition
•Strong genetic predisposition
•Concordance rates in monozygotic twins may approach 100%.
•Marked differences in susceptibility in different ethnic groups
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65. Etiology and pathophysiology
•Type 2 DM
•Environmental and other risk factors
•Diet and obesity
•Middle-aged people with diabetes eat significantly more and
are fatter and less active than their non-diabetic siblings
•The risk of developing type 2 diabetes increases 10-fold in
people with a body mass index (BMI) of more than 30 kg/m2
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66. Clinical pearl!
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However, although the majority of individuals with
type 2 diabetes are obese, only a minority of obese
people develop diabetes, as most obese people are
able to increase insulin secretion to
compensate for the increased demand resulting
from obesity and insulin resistance.

67. Etiology and pathophysiology
•Type 2 DM
•Environmental and other risk factors
•Age
•Type 2 diabetes is more common in middle-aged and older
individuals.
•In the UK, it affects 10% of the population over 65, and over
70% of all cases of diabetes occur after the age of 50 years.
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68. Etiology and pathophysiology
•Type 2 DM
•Environmental and other risk factors
•Ethnicity
•Ethnic origin is a major risk factor for development of diabetes
•This variation in prevalence reflects a number of different
factors, including a higher BMI and lower socioeconomic class
in high-risk groups, differences in health behaviour, e.g.
decreased physical activity and increased smoking; and
differences in genetic risk.
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69. Etiology and pathophysiology
•Type 2 DM
•Metabolic disturbances in type 2 diabetes
•Slow onset of ‘relative’ insulin deficiency
•Lipolysis and proteolysis are not unrestrained and weight loss and
ketoacidosis seldom occur
•Hyperglycaemia tends to develop slowly over months or years
•Many cases are discovered coincidentally and a large number are
undetected
•At diagnosis patients are often asymptomatic or give a long history
(typically many months) of fatigue, with or without ‘osmotic symptoms’
(thirst and polyuria).
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70. Your Date Here Your Footer Here
Diabetes mellitus: Clinical
features and Diagnostics

71. Clinical features
•Classic symptoms of hyperglycemia
•Polyuria, which can lead to secondary
 enuresis
and
 nocturia in children 
•Polydipsia 
•Polyphagia
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72. Clinical features
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73. Clinical features
•Nonspecific symptoms
•Unexplained
 weight loss
•Visual disturbances, e.g.,
 blurred vision 
•Fatigue
•Pruritus
 
•Poor
 wound healing
•Increased susceptibility to infections
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74. Clinical pearl!
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Diabetes mellitus should be suspected in patients
with recurrent
 cellulitis, candidiasis, dermatophyte
infections,
 gangrene, pneumonia (particularly tuber
culosis
 reactivation), influenza, genitourinary
infections (UTIs),
 osteomyelitis, and/or vascular
dementia.

75. Clinical features
Type 1 DM Type 2 DM
 
•Often sudden
•Diabetic ketoacidosis (DKA) is the first
manifestation in approx. one-third of
cases.
 
•Alternatively, children may present with
acute illness and classic symptoms.
•A thin appearance is typical for patients
with
 T1DM.
•Typically
 
gradual
•The majority of patients are
 
asymptomatic.
 
•Some patients may present with
a
 hyperglycemic crisis
•Symptoms of complications 
may be the
first clinical sign of disease.
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76. Clinical features
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77. Diagnostics
•Urine glucose
•Testing the urine for glucose with dipsticks is a common
screening procedure for detecting diabetes.
•Glycosuria always warrants further assessment by blood
testing
•The most frequent cause of glycosuria is a low renal
threshold, which is common during pregnancy and in
young people; the resulting ‘renal glycosuria’ is a benign
condition unrelated to diabetes.
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78. Diagnostics
•Blood glucose
•Cheap and highly reliable
•However, blood glucose levels depend on whether the
patient has eaten recently, so it is important to consider
the circumstances in which the blood sample was taken.
•Blood glucose can also be measured with testing sticks that
are read with a portable electronic meter.
•These are used for capillary (fingerprick) testing to monitor
diabetes treatment
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79. Glucometer
These are used for capillary (fingerprick)
testing to monitor diabetes treatment
There is some debate as to whether self-
monitoring in people with type 2 diabetes
improves glycaemic control.
Many countries now offer self-monitoring
only to people with type 2 diabetes taking
sulphonylurea or insulin therapy because of
the risk of hypoglycaemia.
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80. Clinical pearl!
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To make the diagnosis of diabetes, the
blood glucose concentration should be
estimated using an accurate laboratory
method rather than a portable
technique.

81. Diagnostics
•Blood glucose
•Glucose concentrations are lower in venous than arterial
or capillary (fingerprick) blood.
•Whole-blood glucose concentrations are lower than
plasma concentrations because red blood cells contain
relatively little glucose.
•Venous plasma values are usually the most reliable for
diagnostic purposes
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82. Diagnostics
•Glycated haemoglobin
•Glycated haemoglobin provides an accurate and objective
measure of glycaemic control over a period of weeks to
months.
•In diabetes, the slow non-enzymatic covalent attachment of
glucose to haemoglobin (glycation) increases the amount in the
HbA1 (HbA1c) fraction relative to non-glycated adult
haemoglobin (HbA0).
•The rate of formation of HbA1c is directly proportional to the
ambient blood glucose concentration
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83. Diagnostics
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84. Clinical pearl!
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Although HbA1c concentration reflects the
integrated blood glucose control over the
lifespan of erythrocytes (120 days),
HbA1c is most sensitive to changes in
glycaemic control occurring in the month
before measurement.

85. Diagnostics
•Glycated haemoglobin
•HbA1c estimates may be erroneously diminished in
anaemia or during pregnancy, and may be difficult to
interpret with some assay methods in patients who have
uraemia or a haemoglobinopathy.
•It is particularly important to be aware of this in some
developing countries where nutritional deficiency is
common, especially when an absolute cut-off point is
used, e.g. in the diagnosis of diabetes.
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86. Diagnostics
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87. Diagnostics
•Urine and blood ketones
•Acetoacetate can be identified in urine
•Ketonuria may be found in normal people who have been fasting or
exercising strenuously for long periods, vomiting repeatedly, or eating
a diet high in fat and low in carbohydrate.
•Urine ketone measurements are semi-quantitative, awkward to
perform and retrospective (i.e. the urine has accumulated over several
hours).
•Urine ketone measurements do not measure the major ketone found
in blood during diabetic ketoacidosis (DKA), beta-hydroxybutyrate (β-
OHB).
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88. Clinical pearl!
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Ketonuria is therefore
not pathognomonic of diabetes but, if it
is associated with glycosuria, the
diagnosis of diabetes is highly likely.

89. Diagnostics
•Urine and blood ketones
•Beta-OHB can be measured in blood in the laboratory
and also in a fingerprick specimen of capillary blood with a
test stick and electronic meter.
•Whole-blood β-OHB monitoring is useful in assisting
with insulin adjustment during intercurrent illness or
sustained hyperglycaemia to prevent or detect DKA.
•Blood β-OHB monitoring is also useful in monitoring
resolution of DKA in hospitalised patients
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90. Diagnostics
•Urine and blood ketones
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91. Diagnostics
•Islet autoantibodies
•These include GAD, IA-2 and ZnT8.
•These antibodies can be detected in the general population;
the level at which they are called positive does vary by
laboratory but is usually at concentrations greater than the
95th centile or 97.5th centile of the general population.
•These antibodies are highly sensitive for type 1 DM.
•If islet autoantibodies are present at high titre, this can be
supportive of a diagnosis of type 1 diabetes
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92. Clinical pearl!
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These autoantibodies are not
routinely recommended for
the diagnosis of type 1 DM.

93. Diagnostics
•C-peptide
•Can help differentiate between types of diabetes
 
•↑
 
C-peptide
 levels
may indicate
 insulin
resistance
 and hyperinsulinemia → 
T2DM
•↓
 
C-peptide
 levels
indicate an
 absolute
insulin
 deficiency → 
T1DM
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94. Diagnostics
•Urine protein
•Standard urine dipstick testing for albumin detects urinary
albumin at concentrations above 300 mg/L, but smaller
amounts (microalbuminuria) can only be measured using
specific albumin dipsticks or quantitative biochemical
laboratory tests.
•Microalbuminuria or proteinuria, in the absence of urinary
tract infection, is an important indicator of diabetic
nephropathy and/or increased risk of macrovascular disease
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95. Establishing the diagnosis of diabetes
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96. Clinical pearl!
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Diabetes
should not be diagnosed on
capillary blood glucose results.

97. Establishing the diagnosis of diabetes
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98. Clinical pearl!
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The glycaemia cut-off
that defines diabetes is based on the level
above which there is a significant risk of
microvascular complications (retinopathy,
nephropathy and neuropathy).

99. Establishing the diagnosis of diabetes
•Pre-diabetes have blood glucose levels that carry a negligible risk of
microvascular complications but are at increased risk of developing
diabetes.
•Also, because there is a continuous risk of macrovascular disease (atheroma
of large conduit blood vessels) with increasing glycaemia in the population,
people with pre-diabetes have an increased risk of cardiovascular disease
(myocardial infarction, stroke and peripheral vascular disease).
•Patients with pre-diabetes should be advised of their risk of progression to
diabetes, given advice about lifestyle modification to reduce this risk (as for
type 2 diabetes), and have aggressive management of cardiovascular risk
factors such as hypertension and dyslipidaemia
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100. Stress hyperglycaemia
•In some people (especially those with pre-existing insulin resistance or low
β-cell mass/function), an abnormal blood glucose result is observed during
acute severe illness, such as infection or myocardial infarction.
•This ‘stress hyperglycaemia’ is a consequence of hormones, such as
cortisol and catecholamines, antagonising the action of insulin and
thereby increasing insulin resistance.
•It usually disappears after the acute illness has resolved, but affected
individuals have a significantly increased risk of type 2 diabetes in
subsequent years.
•A similar mechanism explains the occurrence of diabetes in some people
treated with glucocorticoids (steroid-induced diabetes).
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101. Your Date Here Your Footer Here
Principles of
Management

102. Management
•The aims are to improve symptoms of
hyperglycaemia and minimise the risks of long-term
microvascular and macrovascular complications.
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103. Management
•General principles
•Main goal: 
blood glucose control, tailored to glycemic targets and regularly monitored
•Patients with
 
T1DM always
 
require
 
insulin
 
therapy.
 
•T2DM may be managed with noninsulin
 antidiabetics and/or insulin therapy.
•Acute illness may require temporary changes in treatment (e.g., increased
 insulin demand due to 
acute
stress reaction).
•Comprehensive diabetes care 
(all patients)
•Continuous patient education
 
•Lifestyle modifications, including:
•Weight reduction
•Balanced diet and nutrition
 (including a high-fiber diet)
•Regular exercise
•Smoking cessation
•Routine screening for and management of common comorbidities and complications
•Vaccinations including
 influenza, hepatitis B, pneumococcal vaccines, and COVID-19
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104. Clinical pearl!
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Patients with type 2 diabetes who
present with marked symptomatic
hyperglycaemia or DKA will require initial
management with insulin treatment.

105. Management
•General principles
•Risk assessment and prevention
•Control of blood pressure and blood lipids
•ASCVD risk assessment
 and ASCVD prevention
•Patients aged
 40–75 years with diabetes mellitus:
Initiate
 moderate-
intensity statin therapy, regardless of lipid levels.
•Assess indications for
 high-intensity statins. 
•Follow-up: Periodically reevaluate the need for further
diabetes self-management education and support
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106. Clinical pearl!
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Diabetes care should
be
 patient-centered and
comprehensive!

107. Management
•Self-assessment of glycaemic control
•In Type 1 DM → regular self-assessment of blood glucose is essential
•In Type 2 DM → not needed unless taking insulin, sulphonylureas or
during an acute illness
•Insulin-treated patients should be taught how to monitor their own
blood glucose (
 at fixed times  or as necessary) using capillary blood
glucose meters .
•Immediate knowledge of blood glucose levels can be used by patients
to guide their insulin dosing and to manage exercise and illness.
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108. Glucometer
These are used for capillary (fingerprick)
testing to monitor diabetes treatment
There is some debate as to whether self-
monitoring in people with type 2 diabetes
improves glycaemic control.
Many countries now offer self-monitoring
only to people with type 2 diabetes taking
sulphonylurea or insulin therapy because of
the risk of hypoglycaemia.
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109. Management
•HbA1c
 monitoring
•HbA1c
 is measured at fixed intervals.
•At least every
 6 months if targets are met
•At least every
 3 months in the following situations:
•If targets are not met
•If treatment has recently been modified
•If the patient is undergoing
 intensive insulin therapy
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110. Management
•Therapeutic goals
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Common glycemic targets
HbA1C < 7%: suitable for most patients
Fasting glucose levels 5–7 mmol/L (90– 126 mg/dL) is optimal
Pre-meal levels 4–7 mmol/L (72–126 mg/dL) is optimal
2-hour post-meal levels 4–8 mmol/L (72–144 mg/dL) is optimal

111. Clinical pearl!
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Glycemic targets should be
individualized!

112. Management
•Therapeutic goals
•In general, the benefits of lower target HbA1c (primarily, a
lower risk of microvascular disease) need to be weighed
against any increased risks (primarily, hypoglycaemia in
insulin-treated patients).
•HBA1C target early on in diabetes (i.e. patients managed by diet
or one or two oral agents) is 48 mmol/mol or less.
•HBA1C target in older patients with pre-existing cardiovascular
disease, or those treated with insulin is 58 mmol/mol or less.
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113. Time course of changes in
HbA1c during the United
Kingdom Prospective
Diabetes Study (UKPDS)
In the UKPDS there was loss of
glycaemic control with time in patients
receiving monotherapy, independently
of their randomisation to conventional
or intensive glycaemic control,
consistent with progressive decline in β-
cell function.
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114. Management
•Management of dyslipidemia
•There is a reduction in cardiovascular risk even with normal
cholesterol levels, but statin therapy is usually recommended
when the 10-year cardiovascular event risk is at least 20%.
•As a rule, anyone with type 2 diabetes who is over the age of 40
years should receive a statin, irrespective of baseline cholesterol
levels.
•Management of hypertension
•The target for blood pressure is usually below 140/80 mmHg,
although some guidelines suggest 130/80 mmHg.
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115. Management
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116. Management
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117. Clinical pearl!
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Weight loss in overweight and
obese individuals with diabetes markedly
improves glycaemic ccontrol and slows
diabetes progression.

118. Management
•Weight management
•In patients with diabetes, weight management is important, as a
high percentage of people with type 2 diabetes are overweight or
obese, and many antidiabetic drugs, including insulin, encourage
weight gain.
•Obesity, particularly central obesity with increased waist
circumference, also predicts insulin resistance and cardiovascular
risk.
•Weight loss can be achieved through a reduction in energy intake
and an increase in energy expenditure through physical activity.
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119. Management
•Weight management
•Lifestyle interventions or pharmacotherapy for obesity, when
associated with weight reduction, have beneficial effects on
HbA1C, but long-term benefits in terms of glycaemic control
and microvascular disease have not been adequately assessed.
•More recently, bariatric surgery has been shown to induce
marked weight loss in obese individuals with type 2 diabetes
and this is often associated with significant improvements in
HbA1c and withdrawal of or reduction in diabetes
medications.
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120. Management
•Exercise
•All patients with diabetes should be advised to achieve a significant
level of physical activity and to maintain this in the long term
•The American Diabetes Association recommends that all adults with
diabetes are encouraged to reduce sedentary time, and suggest that
adults over 18 years of age should do either 150 minutes per week
of moderate-intensity exercise or 75 minutes per week of vigorous-
intensity exercise, or a combination thereof.
•Muscle strengthening (resistance) exercise is recommended on 2 or
more days of the week
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121. Clinical pearl!
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Physical exercise
reduces
 
blood glucose 
and
increases
 
insulin sensitivity.

122. Management
•Smoking and alcohol
•Recommend
 
smoking cessation 
for all patients; offer
counseling if necessary.
•Alcohol
 consumption
•Should be limited to a moderate intake
 
•To avoid
 hypoglycemia, consume alcohol together with food
and monitor glucose after consumption
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123. Management
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124. Management
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125. Your Date Here Your Footer Here
Antidiabetic drugs

126. Antidiabetic drugs
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127. Antidiabetic drugs
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128. Antidiabetic drugs
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Metformin
Mechanisms of action Suppresses gluconeogenesis by the liver
Increases insulin-mediated glucose utilization in peripheral tissues,
particularly after meals
Various debated mechanisms within the gut
Major advantages Most effective oral agent
Does not cause hypoglycemia
Low cost
Contraindications Chronic kidney disease:
Do not initiate if eGFR < 45 mL/minute/1.73 m²
Do not continue if eGFR < 30 mL/minute/1.73 m²
Severe liver disease
Those who drink alcohol in excess
Common side effects Gl side effects (e.g. diarrhea, nausea), mitigated by slow titrations
B12 deficiency (consider routine monitoring)
Initial concerns about causing lactic acidosis appear to be overstated

129. Clinical pearl!
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Metformin is first-line
therapy for type 2 diabetes,
irrespective of body weight.

130. Clinical pearl!
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Metformin should be omitted temporarily during
any acute illness where acute kidney injury is
possible, as this greatly increases the risk of lactic
acidosis; insulin treatment may be required while
metformin is withheld

131. Antidiabetic drugs
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SGLT-2 Inhibitors
Mechanisms of action Inhibits SGLT2 (sodium/glucose cotransporter 2) in the proximal tubule,
blocking reabsorption of filtered glucose (leading to osmotic diuresis)
Examples Empagliflozin
Dapagliflozin
Canagliflozin
Major advantages Weight loss (~2-3kg)
Empagliflozin and canagliflozin CV mortality in high risk patients with
T2D + atherosclerotic heart disease
All 3 heart failure hospitalizations and progression of nephropathy
Contraindications eGFR < 30 mL/minute/1.73 m² (for first initiation of use)
Common side effects AKI (likely from hypovolemia)
GU infection (e.g. UTIs, vulvovaginal candidiasis)
Euglycemic diabetic ketoacidosis (DKA)
Canagliflozin ↑ risk of lower limb amputation and bone fractures

132. Glucose filtration and
reabsorption
by the nephron
Some 90% of filtered glucose is
reabsorbed by sodium and glucose
transporter 2 (SGLT2) and 10% by
SGLT1. SGLT2 inhibitors reduce net
reabsorbed glucose by 25%. For a mean
plasma glucose of 8 mmol/L (144
mg/dL), this results in a glucose loss of
approximately 80 g per day in the urine,
which in turn reduces plasma glucose.
This equates to 320 kcal per day and
subsequent weight loss.
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133. Antidiabetic drugs
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GLP-1 Receptor Agonists
Mechanisms of action Stimulate glucose-dependent insulin release from the pancreas
Examples Exenatide, Twice/day or weekly injection (ER version)
Liraglutide, Daily injection
Dulaglutide, Weekly injection
Semaglutide, Weekly injection or daily tablet
Major advantages Weight loss (~1.5-2.5kg)
Liraglutide, dulaglutide, and semaglutide variety of adverse CV
outcomes in high risk patients with T2D + atherosclerotic heart disease
Contraindications Personal or family history of medullary thyroid cancer
Personal history of pancreatitis
Common side effects Gl side effects (e.g. diarrhea, nausea, worsen preexisting gastroparesis?)
Association with pancreatitis (though not definitively cause/effect)
May ↑ risk of medullary thyroid cancer

134. Antidiabetic drugs
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DDP-4 Inhibitors
Mechanisms of action Inhibits DPP-4 (dipeptidyl peptidase 4), which normally inactivates GLP-1
and GIP.
Examples Sitagliptin, Once/day tablet
Saxagliptin, Once/day tablet
Linagliptin, Once/day tablet
Major advantages Well tolerated
Nothing specific
Contraindications Recommended to avoid combination therapy with GLP-1 receptor agonist
Personal history of pancreatitis
Saxagliptin is contraindicated in heart failure
Common side effects Joint pains, myalgias
Association with pancreatitis (though not definitively cause/effect)
Saxagliptin is associated with ↑ risk of heart failure hospitalizations

135. Clinical pearl!
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Unlike sulphonylureas, both incretin-based therapies
promote insulin secretion only when there is a glucose
‘trigger’ for it. Thus, when the blood glucose is normal, the
insulin secretion is not augmented and so these agents do
not cause hypoglycaemia when used as monotherapy or
with other drugs that do not cause hypoglycaemia.

136. Antidiabetic drugs
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Sulfonylureas
Mechanisms of action Binds to the ATP-sensitive potassium channel in pancreatic
beta cells, triggering insulin release
Examples Glipizide
Glimepiride
Glyburide
Major advantages Inexpensive
Contraindications Glyburide is contraindicated in CKD
Common side effects Weight gain
Hypoglycemia

137. Clinical pearl!
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Glibenclamideis long-acting and prone to
inducing hypoglycaemia, so should
be avoided in older patients.

138. Antidiabetic drugs
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Thiazolidinediones
Mechanisms of action TZDs enhance the actions of endogenous insulin, both directly
(in the adipose cells) and indirectly (by altering release of
‘adipokines’, such as adiponectin, which alter insulin sensitivity
in the liver)
Examples Pioglitazone
Major advantages Effective in insulin-resistant patients
Beneficial effect in reducing fatty liver and NASH
Contraindications History of heart failure
Moderate-severe hepatic impairment
History of fracture or at high risk for fracture
Active or history of bladder cancer
Common side effects Weight gain
Exacerbate cardiac failure by causing fluid retention
Increases the risk of bone fracture
increases the risk of bladder cancer

139. Antidiabetic drugs
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140. Antidiabetic drugs
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141. Antidiabetic drugs
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142. Do you have any questions?
THANK YOU!