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Diabetes mellitus
Diabetes mellitus refers to a group of common metabolic disorder that shares the phenotype of
hyperglycaemia
...
Hyperglycaemia in diabetes results from defect in :
•
•
•
•
Insulin secretion
Insulin action
Decrease glucose utilisation
Increase glucose production
The metabolic dysregulations related with diabetes mellitus causes secondary pathophysiological
changes in multiple organ system that further causes tremendous burden on the individual's
health
...
Further it also predisposes an individual to various
major cardiovascular diseases
...
With an increasing incidence worldwide,
diabetes mellitus is likely to be one of the leading causes of morbidity and mortality
...
There
are two broad class categories of diabetes mellitus designated as type one and type two
...
Type one diabetes mellitus is the result of
complete or near total insulin deficiency
...
Distinct genetic and metabolic effects in
insulin action and/or secretion gave rise to common phenotype of hyperglycaemia in type
2 diabetes mellitus
...
• The term insulin dependent diabetes mellitus that is IDDM and non insulin dependent
diabetes mellitus that is NIDDM are absolute terms
...
A second difference is that age or treatment
modality is progresteria
...
It is estimated that between 5 and 10% of individual who develop DM after age of 30 years
have type 1 DM
...
OTHER TYPES OF DM :
• Other etiologies of diabetes mellitus include specific genetic defect In insulin secretion or
action, metabolic abnormalities that impaired insulin secretion, mitochondrial
abnormalities, and a host of conditions that impaired glucose tolerance
...
• Diabetes mellitus can result from pancreatic exocrine disease when the majority of
pancreatic islets are destroyed
...
Hormones that antagonise insulin action can also lead to diabetes mellitus
...
Viral infections have been implicated in pancreatic islet destruction but are an
extremely rare cause of DM
...
GESTATIONAL DIABETES MELLITUS
• Glucose intolerance developing during pregnancy is classified as gestational diabetes
mellitus (GDM)
...
DIABETES MELLITUS TYPE 2
IN THE NORMAL CONDITIONS : REGULATION OF GLUCOSE
HOMEOSTASIS
Overall glucose homeostasis :
• Glucose homeostasis reflects a balance between hepatic glucose production and
peripheral glucose uptake and utilization
...
• The organs that regulate glucose and lipids communicate by neural and humoral
mechanisms with fat and muscle producing adipokines, myokines, and metabolites that
influence liver function
...
• Glucagon, secreted by pancreatic alpha cells when blood glucose or insulin levels are low,
stimulates glycogenolysis and gluconeogenesis by the liver and renal medulla
...
Insulin, an anabolic hormone,
• promotes the storage of carbohydrate and fat and protein synthesis
...
• Other tissues, most notably the brain, use glucose in an insulin-independent fashion
...
), and bone also influence glucose homeostasis
...
It is initially synthesized as a
single-chain 86-amino-acid precursor polypeptide, preproinsulin
...
Proinsulin
is structurally related to insulin-like growth factors I and II, which bind weakly to the insulin
receptor
...
• The mature insulin molecule and C peptide are stored together and co-secreted from
secretory granules in the beta cells
...
Human insulin is
produced by recombinant DNA technology; structural alterations at one or more amino
acid residues modify its physical and pharmacologic characteristics
...
Unextracted insulin enters the systemic circulation where it binds to receptors in
target sites
...
• IRS and other adaptor proteins initiate a complex cascade of phosphorylation and
dephosphorylation reactions, resulting in the widespread metabolic and mitogenic
effects of insulin
...
g
...
Activation
of other insulin receptor signaling pathways induces glycogen synthesis, protein
synthesis, lipogenesis, and regulation of various genes in insulin-responsive cells
...
➢ Obesity, particularly visceral or central (as evidenced by the hip-waist ratio), is very common
in type 2 DM (≥80% of patients are obese)
...
➢ As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in
certain individuals are unable to sustain the hyperinsulinemic state
...
A further decline in
insulin secretion and an increase in hepatic glucose production lead to overt diabetes with
fasting hyperglycemia
...
Although both insulin resistance and impaired insulin
secretion contribute to the pathogenesis of type 2 DM, the relative contribution of each varies
from individual to individual
...
e
...
g
...
7–6
...
90 mmol/L) and/or a triglyceride level >250 mg/dL (2
...
Glucose tolerance can be assessed using :
• the fasting plasma glucose (FPG)
• the response to oral glucose challenge
• the hemoglobin A1c (HbA1c)
...
7% are considered to define normal glucose tolerance
...
5% warrants the diagnosis of DM
...
Abnormal glucose homeostasis is defined as :
• FPG = 5
...
9 mmol/L (100–125 mg/dL), which is defined as impaired fasting glucose
(IFG);
• plasma glucose levels between 7
...
7–6
...
An HbA1c of 5
...
4%, IFG, and IGT do not identify the same individuals, but individuals in all
three groups are at greater risk of progressing to type 2 DM, have an increased risk of
cardiovascular disease, and should be counseled about ways to decrease these risks
...
These values for the fasting plasma glucose, the glucose
following an oral glucose challenge, and HbA1c are continuous variables and not discrete
categories
...
SCREENING
Widespread use of the FPG or the HbA1c as a screening test for type 2 DM is recommended
because:
• A large number of individuals who meet the current criteria for DM are asymptomatic and
unaware that they have the disorder
...
• Some individuals with type 2 DM have one or more diabetes-specific complications at the
time of their diagnosis
...
The ADA recommends screening all individuals >45 years every 3 years and screening
individuals at an earlier age if they are overweight (BMI >25 kg/m2 or ethnically relevant
definition for overweight) and have one additional risk factor for diabetes
...
COMPLICATIONS ASSOCIATED WITH DIABETES MELLITUS TYPE 2
Microvascular :
➢
➢
➢
➢
Eye disease Retinopathy (nonproliferative/proliferative)
Macular edema
Neuropathy Sensory and motor (mono- and polyneuropathy)
Autonomic Nephropathy (albuminuria and declining renal function)
Macrovascular :
➢ Coronary heart disease
➢ Peripheral arterial disease
➢ Cerebrovascular disease
Others :
➢
➢
➢
➢
Gastrointestinal (gastroparesis, diarrhea)
Genitourinary (uropathy/sexual dysfunction)
Dermatologic Infectious
Cataracts
Apart from screening other tests that are significant in the tracking
and management of diabetes mellitus type 2 are :
HBA1C test :
• This test measures the average amount of glucose attached to Hb, over past 3 months
...
• Also tells us about the seriousness of the contain that further may cause heart disease,
kidney damage and nerve damage
...
• Characterised by :
1
...
High triglycerides
3
...
Raised LDL cholesterol
• Together this is termed as diabetic dyslipidaemia
...
Spot urine creatinine ratio :
• Also known as microalbumin creatinine ratio
• Helps to identify kidney diseases that can occur as a complication of diabetes
...
• Therefore electrolyte disturbances are common in patients with diabetes
• It is the result of an altered distribution of electrolytes related to hyperglycaemia induced
osmotic fluid shift or total body deficits brought about by osmotic diuresis
...
• Along with it raised blood glucose level can promote bacterial growth which can raise the
risk of Urinary tract infections or thrush developing
...
• Diabetes can destroy the sharp vision in this part of the eye, leading to partial vision loss or
even blindness
...
• Therefore it is important to get an eye examination done once in a year for the patients of
diabetes
...
• This examination include assessment of the protective sensation, foot structure, vascular
status, biomechanics and skin integrity to prevent any kind of foot ulceration
...
• Serious cases may even lead to necrosis followed by the need of amputation
...
TREATMENT FOR DIABETES MELITUS TYPE 2 :
• Lifestyle changes to balance energy intake and storage with insulin supply
✓ Weight loss will decrease insulin demand
✓ Exercise will improve insulin sensitivity
• Management of type 2 Diabetes includes
✓ Healthy eating :
1
...
Low glycemic index foods are helpful
✓ Regular exercise
1
...
✓ Blood glucose monitoring
• When lifestyle changes are not adequate to manage blood glucose levels, pharmacological
approaches should be used
• Classes of non insulin drug help :
✓ Increase insulin secretion
✓ Increase insulin uptake by cells
✓ Decrease glycogenolysis
✓ Decrease digestion of starch (especially disaccharides)
✓ Decrease reuptake of glucose by kidney
CLINICAL CASE 1
Patient is a 63 years old lady who was diagnosed with DM 2 years ago
...
She complains of incontinence and has seen a urologist
...
5%
...
Rationale :
METFORMIN is of the class : BIGUANIDE (AMPK activator)
...
This is the major action responsible for the lowering of
blood glucose in diabetes
...
Insulin resistance exhibited by type 2 diabetics
is thus overcome
...
• Interferes with mitochondrial respiratory chain and promotes
peripheral glucose utilisation through anaerobic glycolysis
...
• Promotes weight loss
• Has potential to prevent the macrovascular as well as microvascular
complications of diabetes
...
8 to 1
...
(Source- Protein data bank)
CLINICAL CASE 2
53 years old man, weights: 95kg, height: 5’10’’ and a BMI of 30
...
He denies
any alcohol or drug use, is non smoker but has hepatitis C
...
But has not taken any medication since last 6
months
...
His fingerstick test at the visit was 304mg/dL
...
This is the major action responsible
for the lowering of blood glucose in diabetes
...
Insulin resistance exhibited
by type 2 diabetics is thus overcome
o Glycogen storage in skeletal muscle
o Reduced lipogenesis in adipose tissue and enhance
fatty acid oxidation
...
• Metformin also reduces intestinal absorption of glucose
...
• Reduced HBA1c by 0
...
2%
...
• This drug is suitable for once daily injection to provide
background insulin action
...
• Lower incidence of night time hypoglycemia episodes are
reported in comparison to isophane insulin
...
• And also because of its acidic pH, it cannot be mixed with any
other insulin preparation and must be injected separately
...
• It reduces cholesterol synthesis by 55 to 60%
• As a result in compensatory it increase in LDL receptors s
expression on liver cells and increase the receptor mediated
uptake and catabolism of LDL
• Has additional antioxidant properties
...
• Oral absorption is slow for this drug but complete
...
(Source – Protein data bank)
CLINICAL CASE 3
A 75 years old female who has been diagnosed with DM type 2 since 2013
...
On monitoring glucose randomly
shows average blood glucose levels as 180mg/DL
...
She
had complaints of complete loss of sensation in left foot and now has complains
about loss of sensation in right foot too
...
5%
...
Now she is prescribed with :
•
•
•
•
•
•
Metformin 850mg – 2 daily
Lantus 30-35 units
Novolog (sliding scale)
Lisinopril 2
...
This is the major action responsible
for the lowering of blood glucose in diabetes
...
Insulin resistance exhibited
by type 2 diabetics is thus overcome
o Glycogen storage in skeletal muscle
o Reduced lipogenesis in adipose tissue and enhance
fatty acid oxidation
...
• Metformin also reduces intestinal absorption of glucose
...
• Reduced HBA1c by 0
...
2%
...
• This drug is suitable for once daily injection to provide
background insulin action
...
• Lower incidence of night time hypoglycemia episodes are
reported in comparison to isophane insulin
...
• And also because of its acidic pH, it cannot be mixed with any
other insulin preparation and must be injected separately
...
• The term “sliding scale” refers to the progressive increase in
the pre-meal or night time insulin dose, based on pre-defined
blood glucose ranges
...
➢ LISINOPRIL : It is an antihypertensive drug if the ACE inhibitor class
...
• Absorption is incomplete but unaffected by food
...
• Ensures uniform hypotensive action round the clock
...
• Lowers cholesterol by 20 to 45%
• A greater rise in HDL Cholesterol if low, is noted
...
• It is indicated for the treatment of diabetic neuropathy in this
case
...
He has weight: 75 kgs, height: 5’5’’ and a BMI of 27
...
The recent reports are as follow :
He also had compliant of blur vision, along with low and loss of sensation in his
foot
...
He was recommended for an eye examination
and foot examination
...
This is the major action responsible for the
lowering of blood glucose in diabetes
...
Insulin resistance exhibited by type 2
diabetics is thus overcome
• Glycogen storage in skeletal muscle
• Reduced lipogenesis in adipose tissue and enhance fatty acid
oxidation
...
• Metformin also reduces intestinal absorption of glucose
...
• Reduced HBA1c by 0
...
2%
...
• Vildagliptin is an oral DPP-4 inhibitor approved for the treatment of
type 2 diabetes
...
➢ ATORVASTATIN: it is a HMG-COA REDUCTASE INHIBITOR (STATINS)
• Best tolerated hypolipidaemic drug
...
➢ BIPHAGIS INSULIN ISOPHANE :
• Insulin isophane is an intermediate-acting insulin that starts to work
within 2 to 4 hours after injection, peaks in 4 to 12 hours, and keeps
working for 12 to 18 hours
...
➢ Telmisartan :
• It is an antihypertensive drug
...