L1-2. diabetes lecures.....................................................

DIABETES MELLITUS
ASSISTANT PROFESSOR DR BILAL NATIQ NUAMAN
CONSULTANT ENDOCRINOLOGIST
Al-Iraqia Medical College
2024

 The name diabetes comes from the Greek
word for a syphon; the sweet taste of diabetic
urine was recognized at the beginning of the
first millennium, but the adjective mellitus
(honeyed) was added by Rollo only in the late
eighteenth century.
 Insulin was discovered in 1921 by Banting in
acid- ethanol extracts of pancreas. It was first
used for treatment in January 1922.

Blood glucose homeostasis
 Blood glucose is precisely regulated and maintained
within a narrow range (between 4.0 and 5.4 mmol/L
(72–99 mg/dL)) when fasting. This is essential for
ensuring a physiological continuous supply of glucose
to the central nervous system.
The brain has little capacity to store energy in the form
of glycogen or triglyceride, while the blood–brain
barrier is largely impermeable to fatty acids. Therefore,
the brain depends on the liver for a constant supply of
glucose for oxidation and hence generation of ATP.

 After ingestion of a meal containing carbohydrate,
normal blood glucose levels are maintained by:
suppression of hepatic glucose production
 stimulation of hepatic glucose uptake
 stimulation of glucose uptake by peripheral tissue
 Insulin, the primary regulator of glucose
metabolism and storage , is secreted from
pancreatic β cells into the portal circulation in
response to a rise in blood glucose
 A number of other factors released from the gut
following food intake can augment insulin release,
including amino acids and hormones such as
glucagon-like peptide 1 (GLP-1) and Glucose-
dependent insulinotropic polypeptide (GIP).

 The incretin effect is mainly attributed to the action
of two hormones gut hormones, including glucose-
dependent insulinotropic peptide (GIP) and glucagon-
like peptide 1 (GLP-1). K cells are responsible for the
production of GIP and the L cells for GLP-1.
 As a result, insulin release is greater when glucose is
administered by mouth than when the same rise in
plasma glucose is achieved by intravenous glucose
infusion, a phenomenon termed the ‘incretin’effect
 When intestinal glucose absorption declines between
meals, portal vein insulin and glucose concentrations
fall while glucagon levels rise. This leads to increased
hepatic glucose output via gluconeogenesis and
glycogen breakdown.

 Insulin is the major regulator not only of
glucose metabolism but also of fatty acid
metabolism. High insulin levels after meals
promote triglyceride accumulation.
 In contrast, in the fasting state, low insulin
levels permit lipolysis and the release into the
circulation of FFAs (and glycerol),

 Diabetes is a group of metabolic diseases
characterized by hyperglycaemia resulting from
defects in insulin secretion, insulin action, or
both. Diabetes is distinguished by disturbances
in carbohydrate, fat, and protein metabolism.
 Diabetes is a leading cause of death in the world
with 4.2 million deaths annually, equivalent to
one death every eight seconds.

 Symptoms may be mild or absent among
people with type 2 diabetes for many years,
especially when hyperglycaemia is minimal.
Although the disease may remain
undetected, tissue damage may develop and
therefore diabetes- related complications
may be present at the time of diagnosis .
Chronic hyperglycaemia may impair growth
in children and increase the susceptibility to
certain infections.
 In addition to the classic symptoms, people
with diabetes may present with vague
symptoms such as fatigue, restlessness, and

 Diabetes is associated with the development of long-
term complications that can be divided into two main
types.
 Microvascular complications include retinopathy
(with potential loss of vision), nephropathy (leading to
renal impairment), peripheral neuropathy (with risk
of foot ulcers, amputations, or Charcot joints), and
autonomic neuropathy (causing gastrointestinal,
genitourinary, and cardiovascular symptoms, and
sexual dysfunction) .
 Macrovascular complications include cardiovascular
diseases with increased incidence of atherosclerotic
cardiovascular, peripheral arterial, and
cerebrovascular diseases as well as heart failure.
 Hypertension and dyslipidaemia often coexist in
people with diabetes.

 Diabetes may be diagnosed based on A1C criteria
or plasma glucose criteria, either the fasting
plasma glucose (FPG) value, 2-h glucose (2-h PG)
value during a 75-g oral glucose tolerance test
(OGTT), or random glucose value accompanied
by classic hyperglycemic symptoms (e.g.,
polyuria, polydipsia, and unexplained weight
loss) or hyperglycemic crises

Aetiology and pathogenesis of diabetes
 Type 1 diabetes
Pathology
 Type 1 diabetes is a T cell-mediated autoimmune
disease involving destruction of the insulin-secreting
β
cells in the pancreatic islets.
 The pathology in the pre-diabetic pancreas is
characterised by ‘insulitis’ with infiltration of the
islets by mononuclear cells.
 Islet cell antibodies are present before the clinical
presentation of type 1 diabetes, and their detection
can be useful in confirming a diagnosis of type 1
diabetes

 in type 1 diabetes, there is an absolute
deficiency of insulin because of an immune-
mediated destruction of insulin-producing β
cells in the pancreatic islets of Langerhans.
 In contrast, in type 2 diabetes, concentrations
of circulating insulin are typically elevated,
but there is a relative deficiency of insulin
because there is reduced sensitivity to insulin
in peripheral tissues (due to obesity) and the
β cells cannot make sufficient insulin to
overcome this ‘insulin resistance’.

 Type 1 diabetes is associated with other
autoimmune disorders including thyroid
disease ,coeliac disease , Addison’s disease ,
pernicious anaemia and vitiligo
Genetic predisposition
 Genetic factors account for about one-third of the
susceptibility to type 1 diabetes, the inheritance
of which is Polygenic.
 The HLA haplotypes DR3 and/or DR4 are
associated with increased susceptibility to type 1
diabetes in Caucasians

 Having multiple confirmed islet
autoantibodies is a risk factor for clinical
diabetes.
 Testing for dysglycemia may be used to
further forecast near-term risk.
 When multiple islet autoantibodies are
identified, referral to a specialized center for
further evaluation and/or consideration of a
clinical trial or approved therapy to
potentially delay development of clinical
diabetes should be considered

 Multiple studies indicate that measuring islet
autoantibodies in relatives of those with type
1 diabetes or in children from the general
population can effectively identify those who
will develop type 1 diabetes.

 Type 2 diabetes accounts for around 90% of
cases, while type 1 diabetes accounts for most
of the remainder.
 All forms of diabetes are ultimately a
consequence of absolute or relative insulin
deficiency. Although type 1 and type 2
diabetes share the clinical phenotype of
hyperglycaemia and carry risks of similar
complications, their aetiology and
pathophysiology are very different.

 Type 2 diabetes
Pathology
 Initially, insulin resistance leads to elevated
insulin secretion in order to maintain normal
blood glucose levels. However, in susceptible
individuals, the pancreatic β cells are unable
to sustain the increased demand for insulin
and a slowly progressive insulin deficiency
develops.
 The key feature is a ‘relative’ insulin
deficiency, This contrasts with type 1 diabetes,
in which there is rapid loss of insulin
production and an absolute deficiency,

 Five main elements characterize the
pathophysiology
(1) insulin resistance,
(2) β-cell dysfunction
(3) dysregulated hepatic glucose production (HGP)
(4) abnormal intestinal glucose absorption.
(5) obesity
insulin resistance
 Insulin resistance results from defective
intracellular signalling following binding of insulin
to its receptor.
 This defect results in decreased intracellular glucose
transporter activity

 In the preclinical phase, the pancreatic β cells
compensate for a genetically predetermined peripheral
(skeletal muscle, adipose tissue, and liver) insulin
resistance by producing more insulin
(hyperinsulinemia) to maintain euglycemia. Some
patients are identified at this stage while they are
clinically asymptomatic.
 With time, the β cells gradually fail to compensate for
the progressive increase in insulin resistance (stage of
IGT or IFG; 40% reduction of β-cell mass),
 eventually hyperglycemia becomes clinically manifest
as diabetes mellitus (80% to 90% reduction of β-cell
mass)
 Insulin secretion continues, albeit not in the
hyperinsulinemic range, with resultant relative insulin
deficiency

 Glucotoxicity refers to the effect of chronic
hyperglycemia in decreasing insulin secretion
(through impaired β-cell sensitivity) and insulin
activity (by increasing insulin resistance and insulin
receptor tyrosine kinase activity) and contributes to
the progressive worsening of hyperglycemia.
 Elevated FFA levels, the result of unrestrained
adipose tissue lipolysis in the relative absence of
insulin, also have a toxic effect on β cells
(lipotoxicity) and,
 together with intracellular protein glycation,
contribute further to the failure of β cells .
 FFAs exacerbate hyperglycemia through increased
oxidation in skeletal muscle and liver, where they
decrease glucose utilization and increase
gluconeogenesis, respectively.

30
The Metabolic Syndrome of
Insulin Resistance
Insulin
Resistance
Hypertension DM2/IGT/IFG
Disordered
Fibrinolysis
Complex
Dyslipidemia
 TG, sdLDL
 HDL
Endothelial
Dysfunction
Systemic
Inflammation
Atherosclerosis
Visceral
Obesity
Pradhan et al. JAMA. 2001

31
Visceral vs. Subcutaneous fat
 Visceral (abdominal, omental) fat correlates best
with the co-morbidities of obesity including insulin
resistance and diabetes.

 Many patients with type 2 diabetes have evidence of
fatty infiltration of the liver (non-alcoholic fatty liver
disease (NAFLD) now termed “Metabolic dysfunction-
associated fatty liver disease (MAFLD)”.
 This condition may improve with effective treatment of
the diabetes and dyslipidaemia, but despite this, a few
patients progress to non-alcoholic steatohepatitis (NASH)
and cirrhosis
Pancreatic β-cell failure
 In the early stages of type 2 diabetes, reduction in the
total mass of pancreatic islet tissue is modest. At the
time of diagnosis, around 50% of β-cell function has
been lost and this declines progressively with
deposition of amyloid in the islets Is the most
consistent pathology.

Genetic predisposition
 Genetic factors are important in type 2
diabetes(marked differences in susceptibility in
different ethnic groups and by studies in
monozygotic twins where concordance rates for
type 2 diabetes approach 100%. While it is less
than 40% for type 1 DM)

One useful clinical tool for distinguishing diabetes type is
the AABBCC approach:
 Age (e.g., for individuals <35 years old, consider type 1
diabetes);
 Autoimmunity (e.g., personal or family history of
autoimmune disease or polyglandular autoimmune
syndromes);
 Body habitus (e.g., BMI <25 kg/m2);
 Background (e.g., family history of type 1 diabetes);
 Control (e.g., level of glucose control on noninsulin
therapies); and
 Co-morbidities (e.g., treatment with immune checkpoint
inhibitors for cancer can cause acute autoimmune type 1
diabetes)

 Overlap can occur with DM, thus patients with
type 2 diabetes may present with marked and
rapid weight loss and even diabetic ketoacidosis.
 type 2 diabetes is increasingly diagnosed in
children and young adults.
 Type 1 diabetes can occur at any age, not just in
younger people, and may develop more
insidiously; the presence of pancreatic
autoantibodies confirms the diagnosis of slow-
onset type 1 diabetes, termed latent autoimmune
diabetes of adults (LADA).
 Other causes of diabetes such as MODY, should
not be forgotten, particularly in those presenting
in childhood or as young adults.

 Endocrinopathies
Excess amounts of certain hormones can antagonize
insulin action and lead to diabetes.
Conditions such as acromegaly that is (excess growth
hormone), glucagonoma that is (excess glucagon)
pheochromocytoma that is (excess epinephrine), and
Cushing's syndrome that is (excess cortisol) can cause
diabetes, indeed, diabetes can be exacerbated, especially
in individuals who have preexisting defects in secretion
of insulin.
Conditions like somatostatinomas and aldosteronomas
can induce hypokalemia, which further contributes to
the development and progression of diabetes in affected
individuals

 Maturity-Onset Diabetes of the Young
MODY is frequently characterized by onset of
hyperglycemia at an early age (classically before age
25 years, although diagnosis may occur at older
ages).
MODY is characterized by impaired insulin secretion
with minimal or no defects in insulin action (in the
absence of coexistent obesity). It is inherited in an
autosomal dominant pattern with abnormalities in
at least 13 genes on different chromosomes
identified to date.
The most commonly reported forms are GCK-MODY
(MODY2), HNF1A-MODY (MODY3), and HNF4A-MODY
(MODY1).

Unless there is a clear clinical diagnosis (e.g.,
individual with classic symptoms of hyperglycemia
or hyperglycemic crisis and random plasma glucose
200 mg/dL [ 11.1 mmol/L]), diagnosis requires two
≥ ≥
abnormal screening test results, measured either at
the same time or at two different time points
.

Therapeutic goals
 The target HbA1c depends on the individual patient.
 Early on in diabetes (i.e. patients managed by diet or
one or two oral agents), a target of 48 mmol/mol (6.5%)
or less may be appropriate((primarily a lower risk of
microvascular disease).
 However, a higher target of 58 mmol/mol (7.5%) may be
more appropriate in older patients with pre-existing
cardiovascular disease, or those treated with insulin and
therefore at risk of hypoglycaemia.
 The target for blood pressure is usually below 140/80
mmHg, although some guidelines suggest 130/80 mmHg.
 For lipid-lowering, there is a reduction in cardiovascular
risk with statin treatment even with normal cholesterol
levels,

 As a general rule, this means that anyone with type 2
diabetes who is over the age of 40 years should receive a
statin, irrespective of baseline cholesterol levels.
 Some guidelines suggest a total cholesterol of less than
4.0 mmol/L (~150 mg/dL) and an LDL cholesterol of less
than 2.0 mmol/L (~75 mg/dL)
 Weight management
 Lifestyle interventions or pharmacotherapy for obesity
when associated with weight reduction have beneficial
effects on HbA1c.
 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.

 People with diabetes should be advised to follow
advice on physical activity as for the general
population. Supervised and structured exercise
programmes may be of particular benefit in type 2
diabetes.
 The American Diabetes Association recommends
that all adults with diabetes reduce sedentary time
(avoiding periods >90 minutes) and do either 150
minutes per week of moderate-intensity exercise or
75 minutes per week of vigorous-intensity exercise.
 Muscle-strengthening (resistance) exercise is
recommended on 2 or more days of the week.

Drugs to reduce hyperglycaemia
 the biguanide metformin
 Sulphonylureas
 Thiazolidinediones
 dipeptidyl peptidase 4 (DPP-4) inhibitors,
 glucagon-like peptide 1 (GLP-1) receptor agonists,
 sodium and glucose transporter 2 (SGLT2) inhibitors.
 insulin
Biguanides
Metformin is the only biguanide now available
 first-line therapy for type 2 diabetes, irrespective of body weight.
 Metformin is also given increasingly as an adjunct to insulin therapy in
obese patients with type 1 diabetes.
 Mild gastrointestinal side-effects with metformin, but only
5% are unable to tolerate it even at low dose .
 main effects are on fasting glucose and reduces hepatic glucose production,
may also increase insulin-mediated glucose uptake, and has effects on gut
glucose uptake .

 weight-neutral, does not cause hypoglycaemia
 has established benefits in microvascular disease, thus It
is employed as first-line therapy in all patients.
 The usual maintenance dose is 1 g twice daily
 Metformin can increase susceptibility to lactic
acidosis ,it can accumulate in renal impairment, so the
dose should be halved when estimated glomerular
filtration rate (eGFR) is 30–45 mL/min, and it should not
be used below an eGFR of 30 mL/min.
 Its use is also contraindicated in patients with impaired
hepatic function.
 It should be discontinued, at least temporarily, if any
other serious medical condition develops, especially one
causing
severe shock or hypoxia. In such circumstances,
treatment

Sulphonylureas
 Sulphonylureas are ‘insulin secretagogues’, i.e. they
promote pancreatic β-cell insulin secretion
 There are a number of sulphonylureas., gliclazide
Glibenclamide, however, is long-acting and prone to
induce hypoglycaemia, so should be avoided in the
elderly.
 Other sulphonylureas include glimepiride and glipizide.
 The dose–response of all sulphonylureas is steepest at
low doses; little additional benefit is obtained when the
dose is increased to maximal levels.

Alpha-glucosidase inhibitors
 The α-glucosidase inhibitors delay carbohydrate
absorption
in the gut by inhibiting disaccharidases. Acarbose and
miglitol are available and are taken with each meal
 Both lower post-prandial blood glucose and modestly
improve overall glycaemic control.
 main side-effects are flatulence, abdominal bloating and
diarrhoea
Thiazolidinediones
 TZDs enhance the actions of endogenous insulin, in part
directly (in the adipose cells) and in part indirectly (by
altering release of ‘adipokines’, such as adiponectin,
which alter insulin sensitivity in the liver).
 Plasma insulin concentrations are not increased and
hypoglycaemia does not occur.

 rosiglitazone, was reported to increase the risk of
myocardial infarction and was withdrawn in 2010.
 pioglitazone, does not appear to increase the risk of
myocardial infarction but it does exacerbate cardiac
failure by causing fluid retention, and recent data show
that it increases the risk of bone fracture, and possibly
bladder cancer
 can be very effective at lowering blood glucose in some
patients and appears more effective in insulin-resistant
patients.
 the combination of insulin and TZDs markedly increases
fluid retention and risk of cardiac failure, so should be
used with caution.

 Incretin-based therapies:
 DPP-4inhibitors and GLP-1 analogues
 The incretin effect is the augmentation of insulin
secretion seen when a glucose stimulus is given orally
rather than intravenously, and reflects the release of
incretin peptides from the gut
 The Incretin hormones are primarily glucagon-like
peptide 1 (GLP-1) and gastric inhibitory polypeptide
(GIP).
 These are rapidly broken down by the peptidase DPP-4
(dipeptidyl peptidase 4).
 The incretin effect is diminished in type 2 diabetes,
 The ‘gliptins’, or DPP-4 inhibitors, prevent breakdown
and therefore enhance concentrations of endogenous
GLP-1 and GIP.

 Sitagliptin, was the first among the group, others now
available include
 vildagliptin, saxagliptin and linagliptin. These drugs
are very well tolerated and are weight-neutral
 The GLP-1 receptor agonists have a similar structure
to GLP-1 but have been modified to resist breakdown by
DPP-4. These agents are not orally active and have to be
given by subcutaneous injection.
 they have a key advantage over the DPP-4 inhibitors:
because the GLP-1 activity achieved is supra-
physiological, it delays gastric emptying and, at the level
of the hypothalamus, decreases appetite. Thus, injectable
GLP-1 analogues lower blood glucose and result in
weight loss .
 Currently available GLP-1 receptor agonists include
exenatide (twice daily), Semagltide (once weekly) and
liraglutide (once daily).

Mounjaro® is a dual-action GLP-1/GIP
medication typically prescribed to
treat diabetes and shown to help
people lose an average of 20% of their
body weight
,*.

Insulin therapy
 Until the 1980s, insulin was obtained by extraction and
purification from pancreata of cows and pigs (bovine
and porcine insulins),
 Recombinant DNA technology enabled large-scale
production of human insulin.
 More recently, the amino acid sequence of insulin has
been altered to produce analogues of insulin, which
differ in their rate of absorption from the site of
injection.
 The duration of action of short-acting, unmodified
insulin (‘soluble’ or ‘regular’ insulin), which is a clear
solution, can be extended by the addition of protamine
and zinc at neutral pH (isophane or NPH insulin) or
 excess zinc ions (lente insulins).
 These modified ‘depot’ insulins are cloudy preparations.

 The rate of absorption of insulin (from SC inj.)may be
influenced by many factors other than the insulin
formulation, including the site, depth and volume of
injection, skin temperature (warming), local massage
and exercise.
 Absorption is delayed from areas of lipohypertrophy at
injection sites which results from the local trophic action
of insulin, so repeated injection at the same site should
be avoided.
 intravenous and intraperitoneal inj. are reserved for
specific circumstances.
 plasma insulin concentrations are elevated in patients
with liver disease or renal failure.
 Rarely, the rate of clearance can be affected by binding to
insulin antibodies (induced by use of animal insulins).

Side-effects of insulin therapy
 Hypoglycaemia
 Weight gain
 Peripheral oedema (insulin treatment causes salt and
water retention in the short term)
 Insulin antibodies (with animal insulins)
 Local allergy (rare)
 Lipohypertrophy or lipoatrophy at injection sites

Alternative insulin therapies
 ‘Open-loop’ systems are portable pumps providing
continuous subcutaneous, intraperitoneal or iv infusion
of insulin it can be programmed to match the patient’s
diurnal variation in requirements and then manually
boosted at mealtimes
 these devices requires a high degree of patient
motivation. But its use is limited by cost.

L1-2. diabetes lecures.....................................................

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