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Pathophysiology of insulin resistance

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 Pathophysiology of insulin resistance
Individual Report for Module 1

The Post Graduate Diploma in Diabetes

University of Cardiff, Wales

Written by

Ismat Abdelrhman Alborhan Mohammed

 Introduction
Insulin is a hormone promote anabolism that balances individual caloric needs and intake with
disbursement. Basically it raise store of excess carbohydrate and protein breakdown in forms of lipids
and inhibits the opposite. Insulin resistance is impairment in the function of insulin targets cells such
as liver cell, adipocytes and musculoskeletal cells to react to the insulin action.1 It is collection of
many clinical metabolic disorders such as type 2 diabetes mellitus, hypertension, obesity and
dyslipidaemia clustering known as metabolic syndrome.2 Global incidence of type 2 diabetes mellitus
roughly will be around 250 million individual by the year 2020.3In spite that the basic causing factors
is unknown, it is obvious that insulin resistance act as major part in its development. Judge by
existence of insulin resistance before occurrence of the disease 10 -20 years back. 45

Mechanism of Insulin resistance

Insulin resistance pathologically grow through many interactions of genotype lifestyle change mainly
sedentary life and over eating.67 Physiologically, many circulating factors regulate insulin sensitivity
in target tissue such as adipokines, plasma lipid and circulating hormones plus their signalling
pathways.89 There is neuroendocrine axis involve adipose tissue with brain and gut which regulate
insulin metabolism by adjusting insulin sensitivity in target tissues.10Adipokines are hormone secreted
by adipocytes store where some stimulate and other inhibit insulin sensitivity. In peripheral tissue
insulin action is stimulated by Leptin and adiponectin. on the other hand, TNF, resistin, IL-6, and
retinol binding protein 4 supress insulin sensitivity.11 Although metabolism and nutrition are regulated
by adipocyte derived factors pattern of life, overweight and genetic can disturb this balance.12 It is
found that during obesity there is increase in level of inhibitory adipokines and circulating fatty
acids.8

Factors influence insulin sensitivity:13

Obesity and fat distribution, centrally (abdomen and waist) placed adipose tissue especially in
the viscera are implicated in insulin resistance. Also suspected are two molecular peptides,
Leptin and Adiponectin.
Age. Increase in age reduces insulin sensitivity.
Genetics. Insulin resistance has been attributed to multiple gene mutations which are not well
understood. The few that are known are rare and less than 4%. Example is peroxisome
proliferator activating receptor gamma (PPAR-y). The genetic predisposition starts beta-cell
dysfunction from gestation through early age to adult age.
Exercise and physical fitness.
Dietary nutrients, the world is now moving towards westernized refined carbohydrates and
high fat diet which reduces insulin sensitivity. The release of free fatty acids and their
metabolites elicits inflammatory response with release of cytokines and adipokines which in
turn reduces insulin sensitivity.
Medications like growth hormones, steroids and nicotinic acid reduces insulin sensitivity.

Insulin has so many actions that promote storage of carbohydrates in different forms:14

In Skeletal muscles, it increases cross membrane transport via GLUT4 into the cell for
phosphorylation of glucose and hence synthesis of glycogen.
In the liver, It raises synthesis of glycogen and anew lipogenesis although suppress
gluconeogenesis.
In the adipose tissue, it inhibits lipolysis and raise lipogenesis.
 Causes of insulin resistance
There are many factors lead to development of insulin resistance. The major leading cause are
overweight, sedentary life style and genetic factors. Some other factors contribute in some ways of
development of insulin resistance. Most important are obesity, physical inactivity, and genetic factors.
Other factors that may affect the degree of insulin resistance are diet composition, aging, and
hormones (particularly glucocorticoids and androgens). High-carbohydrate diets reproduce some of
the features of the metabolic syndrome. There are several factors that are postulated after several
studies that cause insulin resistance. There are three main ones that converge on common pathways
that inhibit insulin action. They are:

The accumulation of ectopic lipids and its metabolites,

The development of ER stress and the activation of the unfolded Protein response.
The contribution of systemic low grade inflammation. These are complex metabolic
processes that have been extensively studied.15

The association of ectopic lipid accumulation and insulin resistance has been universally established.
It acts at the glucose transport level GLUT4 at the cell membrane that responds to insulin signalling
thereby impairing insulin signalling. The activation of the unfolded protein response (UPR) also
known as endoplasm reticulum stress which positively gives cells the capacity to adapt to changes
especially the b-cells of islet. But in liver and adipose tissue especially, activation of the Jun-N-Kinase
1(JNK1) causes the serine phosporylation of insulin receptor substrate 1 at a key serine, leading to
impaired insulin signalling.16

Diagnosis
It is inapplicable to measure insulin resistance in isolation. The choice of the test or method used
depend on type and size of study undertaken. Insulin resistance different assessment methods
include:17

Euglycaemic clamp (gold standard)

Short Insulin tolerance test ITT
Homeostatic model assessment HOMA
Continuous infusion of glucose with model assessment CIGMA
Frequently sampled intravenous glucose tolerance test FSIVGTT
Insulin suppression rest IST

The usage of collection routine two laboratory investigations such as fasting insulin plus triglycerides
will give elementary screening for insulin resistance in public population. 18 The standards ways for
measurement of insulin resistance in field of research are intravenous glucose tolerance test (IVGTT)
plus euglycemic insulin clamp on the other hand they are unpractical in clinical daily practice and are
uneasy to carry out in population-based research studies.19
 Management
The main step in management of insulin resistance is nutrition which include low caloric intake to
reverse over weight and obesity plus adjustment of carbs in diet to avoid aggravation of excess
insulin.20 American Diabetes Association (ADA) recommend to start with lifestyle change including
diet modification and exercise as first line for management of type 2 diabetes mellitus. If no
achievement was notice within 3 month, drugs will be the second choice.21 There are around six
hypoglycaemic drugs used such as:22

Insulin
Sulfonylureas,
Meglitinides
Biguanides
Alpha glucosidase inhibitors
Thiazolidinediones

It is unluckily that no perfect drugs is available for treating insulin resistance per sea. While
metformin is the only drug which reduce insulin resistance.23 On the other hand there are some
drugs which potentially lower insulin resistance like thiazolidinediones (troglitazone).24 Although
infrequent liver failure cases have been linked with troglitazone medicament. 25 26

Conclusions
It has been clearly demonstrated that in order to prevent and treat type 2 diabetes effectively we need
to have clear knowledge about insulin resistance and its cellular mechanism. It is more obvious now
insulin resistance is reverse condition which can be achieved by decreasing weight and increasing
physical activity. There is huge global need for strategic plan implementation for appropriate type 2
diabetes mellitus and obesity management.
 Abbreviation
ER endoplasmic reticulum
TNF Tumor necrosis factor-
IL-6 Interleukin 6
PPAR-y peroxisome proliferator activating receptor gamma
GLUT4 Glucose transporter type 4
UPR unfolded protein response
JNK1 Jun-N-Kinase
ITT Insulin tolerance test
HOMA Homeostatic model assessment

CIGMA Continuous infusion of glucose with model assessment

FSIVGTT Frequently sampled intravenous glucose tolerance test

ADA American Diabetes Association

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