CCEBDM_Module_ Diabetes module 1 on T2DM 1.pdf

Diabetes module 1 on T2DM

1. of INDIA DR MONANS DIABETES SPECIALTIES CENTRE

Ze pac, LE Da. Mohan
| (i) ine pe hand

EVIDENCE BASED DIABETES
MANAGEMENT (CCEBDM)

(January 2022 - December 2022)

Module 1:
Introduction to Diabetes Mellitus

| eth int Bd
Koieseres [US]
Na

3. Disclaimer

Public Health Foundation of India (PHFI) and Dr. Mohan's Diabetes Education Academy (DMDEA) do not recommend or provide individualized medical
diagnosis, treatment or advice, nor do they recommend specific therapies or prescribe medication for anyone using or consulting this publication. The
information contained in this publicationisintended for general educational and informational purposes only.

Medical information changes rapidly. Therefore, PHFI and DMDEA assume no responsibility for how readers use the information contained in this publication
andhence assumenolegalliability or responsibility arising out of use of this information.

Contentsincludedin this module are solely provided by designated expertsand represents their viewpointsentirely.

Copyright 2022PublicHealth Foundation of India, New Delhi & Dr. Mohan's!

iabetes Education Academy, Chennai. Allrights reserved.

This training material (including print material, Modules and presentations) isthe exclusive intellectual property right of PHF! and DMDEA. No part of this training

material may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or
otherwise without the prior written permission of PHFland DMDEA.

6. Introduction to the Certificate Course in Evidence Based

Diabetes Management

On behalf of Public Health Foundation of India (PHF!) and Dr. Mohan's Diabetes Education Academy (DMDEA), we wish you a warm welcome to the Certificate
Coursein Evidence Based Diabetes Management (CCEBDM).

The CERTIFICATE COURSE IN EVIDENCE BASED DIABETES MANAGEMENT (CCEBDM) aims to equip primary care physicians with the information and tools needed
o manage diabetes na clinicsetting. The course will be delivered on a modular basis. There are 12 modules, each of which will bedelivered on a weekend of every
month.

Each module consists of the following:

The day's discussions start with a case discussion. Your facilitator may provide the case from his practice or you can present interesting cases that you have seen in
yourclinics.

The case is followed by the pre-test to be conducted on the PHF! Training Division mobile app. This consists of ten multiple choice questions (MCQs) designed to
test the trainees’ baseline knowledge. The same ten MCQs will be administered as a post-test at the end of the day's lectures. Please participate actively in these
sincethey form partof the evaluation criteria

The lecture discussions have been designed to be as interactive as possible. Sufficient time has been allotted for each lecture so as to enable interaction to take
place. Please do feel free to clarify any of the points with your facilitator, who will be happytoassistyouatalltimes.

Case studies forman integral part of the curriculum. As formost thingsinclinical medicine, there might not be ‘ight”or“wrong"answers to mostof the cases, butit
isthe thought processand logicbehind the discussions that we need to stress upon.

Inaddition to the preand posttest, you are expected to submit certain assignments at specified points of time during the course. These are detailed below.

— Pages

7. Module introduction to Diabetes Melitus

+ Interim Assignment 1: To be submitted at the beginning of Module 4
Assignment 1: Describe howyouwillevaluatea 26 year old male presentingwith diabetes for thefirst time?
+ Interim Assignment 2: To be submitted at the beginning of Module 7
Assignment 2: How willyou manage and follow-up anewly diagnosed case of type 2diabetesin yourpractice?
‘+ Interim Assignment 3: To be submitted at the beginning of Module 10
Assignment3: How often doyousee chronic diabetes complications in your practice? What steps will youtaketo prevent them?

‘The curriculum for the CCEBDM has been designed with inputs from eminent endocrinologists and diabetologists from all over India, who form the National
Experts and Faculty for this course. Even though all efforts have been taken to ensure that the information provided is accurate and up to date, you may come
across instances where you find that thisisnot so. We request you to point these out to us so that we can rectify themin timefor thenext session.

As the title suggests, we have tried to incorporate the latest evidence-based guidelines in the curriculum. Wherever possible we have used global guidelines
such as those proposed by the World Health Organisation (WHO) and Intemational Diabetes Federation (IDF). In cases where these are not available or
appropriate, we have adopted the guidelines proposed by other organizations such as the American Diabetes Association (ADA) and the European Association
forthe Study of Diabetes (EASD). We have also included Indian guidelines wherever possible.

‘Weare surethat you will find this Courseinteresting, enjoyableand informative.

Reference Text books

1. Holt RIG et al (eds). Textbook of Diabetes (5” edn). Wiley Blackwell, 2017.
2. DeFronzoRA, FerranniniE, ZimmetP) AlbertiKGMM (eds).International Textbook ofDiabetes Mellitus (4”edn.). Wiley, 2015.
3. Joshi SRetal(eds.)RSSDI Textbook of Diabetes Mellitus (Sth edn.). New Delhi, Jaypee Bros. Medical Publishers, 2020.

We wish you happy learning!

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9. Module introduction to Diabetes Melitus

Learning Objectives

To define diabetes

To learn about some of the important milestones in diabetes and its management
To understand the magnitude of the problem of diabetes and the role of the
primary care physician in tackling it

To understand the basics of normal intermediary metabolism and the hormonal
control of the same

To learn about the pathogenesis and pathophysiology of type 2 diabetes and
appreciate its diverse metabolic consequences

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10. ntroduction to Diabetes Mellitus

Theterm diabetes" which means"to pass through” was first used by the Roman physician Aretaeus in the 2” century A.D. However, descriptions of adisease state
lar to diabetes have been found in much older texts from different parts of the world, The Egyptian Ebers Papyrus, dating back to 1552 BC. is the oldest
reference to a condition resembling diabetes. The ancient Indian medical texts of Charaka and Sushruta 2” and 5” Century A.D. give detailed descriptions of
diabetes its classificationand management.

The later years of the 19” century saw an explosion in the understanding of human physiology and basic biochemistry. Work done by Minkowskiand von Mering,
Paulescu and Moses Barron and others localized the defect in diabetes mellitus to the pancreas. However, it took the seminal work of Banting et alin 1921 to
isolate the exact substance secreted by the pancreas that prevented the development of diabetes. This substance, initially termed “isletin', was later
rechristened “insulin,

The" thick brown muck’ first produced by Banting and Best was far from ideal in many respects. It contained large amounts of impurities and the clinical effect of
each batch was highly variable. Further developments in the 20” century led to the development of improved formulations of insulin in terms of purity (highly
purified and monocomponent insulin) as well as pharmacokinetic properties (NPH and lente insulin). This process culminated in the introduction of human
insulinin the 1980sand insulinanalogues in the last decade of the century.

The field of non-insulin therapies for diabetes also received a boost in the latter half of the 20" century, with theintroduction of biguanides and sulfonylureas. The
last part of the 20” century and the early years of the 21" have seen the introduction of novel molecules such as the thiazolidinediones, alpha glucosidase
inhibitors, incretin based therapies and mostrecently, the SGUT2 inhibitors.

The developments of the last 150 years have made a dramatic difference to the life of a person with diabetes. Type 1 diabetes isno longer invariably fatal. Patients
with type 2 diabetes can nowexpecttolive longer andmorecomfortablythan they ever did in the past. However westill have alongway togo. A curefor diabetes-
beittype 1 ortype 2-i still nowhere in sight. The currently available therapies do not exactly restorenormoglycemia ina physiologic manner- and are not totally
devoid of side effects, either. In spite of our best efforts, diabetes complications claim millions of lives every year. And the number of people with diabetes
continues its inexorable rise. Itisto be hoped that research being undertaken today all around the world will provide solutions to these issues within our lifetime.
Afterall, we have overcome farmore difficult obstaclesin the past!

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11. Module introduction to Diabetes Melitus

1.2 Defi

In 1997, the American Diabetes Association (ADA) defined diabetes as a group of metabolic disorders characterized by hyperglycemia resulting from defects in
insulin secretion, insulin action or both’. This definition has been accepted by other international bodies like World Health Organisation (WHO). For the purposes of
this course, we have modified the definition as follows.

n of Diabetes Mellitus

Theterm diabetes mellitus describes a metabolic cum vascular syndrome of multiple etiology characterized by chronic hyperglycemia with disturbances
of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both leading to changes in both small blood
vessels (Microangiopathy) and large blood vessels (Macroangiopathy).

‘This definitionis usefulinthatit conveysa sense of the etiology, pathogenesis, biochemical features and implications of diabetes mellitus.

1.3 Epidemiology of Diabetes

Diabetes mellitus is the most common metabolic disorder in the world. According to the IDF, 537 million people in the world live with diabetes as of 2021. In
most countries, the number of individuals with diabetes is steadily increasing.

China has thelargest number ofpeople with diabetes in the world (140.8 million), followed byindiawith 74.1 million Table 1).

Prevalence rates of diabetes have been found to be high in certain isolated populations like the Pima Indians of Arizona and the Pacific Island populations. Asian
Indians have been consistently found to havea higher prevalence of diabetes in moststudies.

Most people with diabetes have type 2 diabetes. Type 1 diabetes constitutes around 5% of the total number of individuals with diabetes, and the number is only
slowly increasing. The prevalence of type 1 diabetes is highest in northern Europe and low in Africa and Asia. The other forms of diabetes are rare throughout the
world.

In India the prevalence rates of diabetes have increased dramatically since the time the first national survey was undertaken, in 1971. At that time the prevalence
was 2.3% in the urban areas and 1.2% in theruralareas. The most recent studies suggest prevalencerates of between 15 to 20% in urban areasand about halfofthat
inruralareas.

Table 1: Diabetes - Top five countries in 2021

No of people with diabetes (in millions)

China 1408
India 741
Pakistan 329
United States 322
Indonesia 194

Diabetes Atlas (10” edn), Intemational Diabetes Federation, 2021. Page

12. Certificate Course in Evidence Based Diabetes Management (CCEBOM)

‘Thereasons for the explosive increasein the prevalence of diabetesin India have been the subject of much study. Whilea high level of genetic predisposition does
play a role, itis unlikely that the genetic makeup of the population has changed so drastically in the past 30 years as to account for the alarming increase in
prevalence of diabetes. More likely, increasing prosperity and urbanisation have led to wholesale changes in lifestyle which cause diabetes to manifest in
individuals who already havea genetic predispositionto the disease.

1.4 Role of Primary Care Physician in Tackling India's Diabetes Epidemic

Indias currently in the grip of an explosive epidemic of type 2 diabetes. We already have more than 74 million people living with diabetes in India, as perthe latest statistics. It
iseven more worrying that more than 50% of individuals with diabetes remain unaware that they have this condition,

Arecent study from Chennaithrew up somealarming facts about the awareness-or lack ofit- about diabetes in urban India. Up to 25% of the general population had
never heard of diabetes. Even fewer people knew about the risk factors for diabetes, Even among educated professionals (doctors included), more than 40% did not
know that diabetes canbe prevented. Even people with diabetes were unaware that the disorder can affect other organsinthe body.

Recent studies show that more than 60% of individuals with diabetes had unsatisfactory control of blood glucose and that essential tests like HbA1c were being
routinely left out of prescriptions. Ths reflects lack of awareness on partof both the patientas well as health care provider.

Thediabetes epidemic hasnow moved outofthe metropolitan cities and affected the smaller townsaswell.Very soon our villages will alsofall prey toit.

‘The Government of india has recognized the threat posed by diabetes to the health of the nation as early as 1987, and started the National Diabetes Control Program.
Inrecent yearsit has been recognized that diabetes, cardiovascular disease and stroke share the same risk factors and that an approach aimed at tackling all the three
major noncommunicable diseases (NCDs) will give the greatest yield. Thus was born the National Programme for Prevention and Control of Diabetes, Cancer,
Cardiovascular Disease and Stroke (NPCDCS).This programme aims at reducing the risk factors for NCDs and atearly and effective treatment of individuals with NCDs.
It plans to achieve these goals through interventions based at the workplace, schools and community. It also aims to make the private sector a key player in the
programme. The pilot phase ofthis programme was launched in January 2008 in ten districts across the country and has covered all districts of the country by theend
ofthe 12° fiveyearplan.

Itis practically impossible or the Government to deal with the epidemic of diabetes on its own. So individual medical practitioners will continueto play a major rolein
detecting and managing diabetes inthe community. n India we donot have sufficient numbers of trained endocrinologists to treat the huge number of patients with
diabetes. Moreover these professionals tend to be concentrated in the larger cities, and as such they are inaccessible to the majority of rural dwellers. Therefore, ifthe
diabetes epidemic is to be successfully tackled, every practising physician should acquire a working knowledge of diabetes. By virtue of patient acceptability,
availability and affordability, primary care physicians re ideally placed to treat the majority of diabetes patients in this country.

Unfortunately, diabetes and related disorders like hypertension and cardiovascular disease have so far been neglected in the undergraduate and postgraduate
medical curriculum. This hasled to the fresh medical graduate or postgraduate being ill-equipped to treat these patients, who will form the bulk of his practice.

The need of the hour is to train general physicians and interested general practitioners in the basics of diabetes management, so that they gain confidence and
expertise in managing these patients and prevent them from developing complications.

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13. Module introduction to Diabetes Melitus

1.5 Normal Glucose Metabolism

Carbohydrates are the main sources of energy in the body. Glucose is the ubiquitous carbohydrate which can be utilized by most ofthe tissues in the body as an energy
source, either exclusively (asin thecase of brain) oras.a supplemental source (asin cardiac muscle).

1.5.1 Digestion and Absorption of Carbohydrates

The main sources of carbohydratein the diet are starch (from foods of plant origin), sucrose (cane sugar or beet sugar) and fructose (found in fruits). Most of these foods
are complexcarbohydrates which have to be broken down into simpler units beforethey can be absorbed.

The process of digestion of carbohydrate occurs chiefly in the small intestine and toa lesser extent in the stomach. The main digestive enzymes involved are the salivary and
pancreatic amylases and the various disaccharidases (sucrase, lactase, maltase) foundin the intestinal juice.

‘The metabolic pathways of glucose depend on whether the individualis ina fed state or fasted state. In the fed state ie. not needing energy over and beyond the basal
metabolic rate, the entire biochemical system is directed towards storage of absorbed nutrientsin the form of glycogen or fat. These processes are called glycogenesis
and lipogenesis respectively and both of them are promoted by insulin. However even in the fed state, if the body is in need of energy (eg during a brisk walk after
meals) then the various biochemicalprocesses are directed towards generation of energy in the form of ATP by metabolism of glucose. The first step of this process,
called glycolysis, involves the catabolism of glucose to pyruvate and release of ATP. Although the amount of energy released during this process of glycolysis is small
(2ATP per molecule of glucose), thishas the following advantages:

© Thisprocess is very fast.

It does not need aerobic environment.
In the fed state, whether insulin will promote formation of glycogen or will promote catabolism of glucose into pyruvate by glycolysis, will depend on the need of the
body. In the fasted state, the processes are directed towards breaking down the energy depots and ensuring a constant supply of glucose to the brain and of other
metabolicfuelsto the othertissues.

‘The main storage form of glucose in animals is glycogen. This complex carbohydrate, made up of repeating units of glucose, is found chiefly in the liver and skeletal
muscles. In the liver it contributes to the hepatic glucose output during the fasting state, whereas in the skeletal muscle it acts as a readily available source of energy
duringmuscle contraction,

During muscle contraction, large amounts of lactate are generated from glycogen by means of anaerobic glycolysis. This lactate is transported into liver, where itis
reconvertedto pyruvate and thence to glucose. This processis a gluconeogenic mechanism whereby the blood glucose levels are kept constant even during strenuous
physical activity. The lactatecycleisalsoknownas Cor cycle.

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14. Cerficae Course in Evidence Based Diabetes Management (CCEBDM)
Other substrates for gluconeogenesis include the glucogenic amino acid alanine and the glycerol part of neutral fat. in addition to liver, kidney is another major site
forgluconeogenesis. However, liveris the only organ which can release free glucose into the systemic circulation.

1.5.3 Hormonal Control of Blood Glucose Levels
For optimalfunctioning ofall organs, particularly the brain, itis essential that the blood glucose concentrations be maintained within a normal range. Thisrequires

the co-ordinated action of various hormones acting in concert. The only hormone which brings down the blood glucose levels is insulin, Arrayed against itare a
group of molecules commonly termed ‘counterregulatoryhormones” (Figure).

Figure 1
Hormonal Control of Blood Glucose Levels

Decrease Blood Glucose Increase Blood Glucose (counter regulatory hormones)

INSULIN PROMOTES, GLUCAGON
+ Glycogenesis Promote glycogenolysis*
+ Lipogenesis
Protein synthesis
INSULIN INHIBITS GLUCOCORTICOIDS
Gluconeogenesis Promote gluconeogenesis*

Protein break down

Lipolysis GROWTH HORMONE AND CATECHOLAMINES.
Promote glycogenolysis and gluconeogenesis

*predominant action

In the fed state insulin promotes the glucose-utilising and energy-storing processes (glycogen synthesis, fat synthesis, protein synthesis) and inhibits glucose-
producing processes (glycogenolysisand gluconeogenesis) and lipolysis (Figure 2).

Page 4

15. In the fasted state, the blood glucose levels are prevented from going too low by a combination of

Carbohydrate Metabolism in the Fed State
(Process Promoted By Insulin)

Module introduction to Diabetes Melitus

DIETARY CARBOHYDRATE

Digestion & absorption

GLUCOSE — MINOR PATHWAY‘

| iycogenesis | Giycoiysis
GLYCOGEN PYRUVATE
y

ACETYL COENZYME A

| Fatty acid synthesis

FATTY ACIDS

+
TRIGLYCERIDES

counterregulatory hormones (Figure 3).

release and increased action of

Page 15 —

16. Cectiate Course in Evidence Based Diabetes Management (CCEBDM

Figure 3
Carbohydrate Metabolism in the Fasting State
(Process Promoted by Counter Regulatory Hormones)

=
Lu S a
Glucose
(Obligate Fuel for Brain) =, EVE
1 m
Glucogenic Amino Acids

x
ca
y
et a
y
1. Glycogenolysis Ketone Bodies
2. Gluconeogenesis (Fuel for Cardiac Muscles)

Insulin is a polypeptide hormone secreted by the B cells of the islets of Langerhans of the pancreas. Insulin is synthesized as a much larger precursor known as
preproinsulin, which gets broken down to proinsulin, which in turn is cleaved to form equimolar concentration of insulin and C-peptide (or connecting peptide,
Which will be describedinalatermodule).Insulinthus synthesizedis storedin secretory vesicles in the cytoplasm of the B cell (Figure4).

1.5.3.1 Insulin

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17. Module introduction to Diabetes Melitus

Figure 4
Processing of Proinsulin to Insulin and C-peptide

ss y Zi (Vo,

yas à
‘connie

Ta

ae

When the organism is replete with glucose, e.g. after a meal, glucose enters the ß cell through an insulin-independent transporter, glucose transporter-2 (GLUT-2).
Glucose is metabolized by the enzyme glucokinase to yield energy in the form of adenosine triphosphate (ATP). High levels of ATP in thecell lead to closure ofa special
transporter on the cell membrane called K-ATP (ATP sensitive potassium channel) leading to accumulation of potassium ions in the cytoplasm and depolarization of
thecell.Thisin turn leads to opening of calcium channels influxof calcium ions intothe celland release of insulin from the secretory vesicles intothe extracellular fluid
andthenceintothe blood,

Glucokinase acts as the glucose sensor of the B cell. Inactivating mutations of this enzyme lead to failure of the B cell to secrete insulin even in the face of elevated
blood glucose concentrations. The heterozygous state for this mutation underlies most of the cases of maturity onset diabetes of the young, type 2 (MODY 2), a
monogenic form of diabetes. Conversely, activating mutations can lead tohypoglycemia.

Sulfonylurea drugs act by closing the K-ATP channel, independent of glucose or ATP. They do so by binding to the SUR (Sulfonylurea receptor site) subunit of the
potassium channel. Thenon-sulfonylurea secretagogues (repaglinide, nateglinide) also act by closing the potassium channel, but they do so by bit
site from thesulfonylureas.

In addition to glucose, insulin secretion can be stimulated by certain amino acids (particularly leucine), glucagon, incretin hormones (GLP-1 and GIP) and
parasympathetic stimulation. Inhibitors of insulin include insulin itself, sympathetic stimulation and drugs lke diazoxide. In a normal individual the most potent
stimulus for suppressing insulin secretion isa fallin the blood glucose levels.

Insulin secretion in response toa glucose load occursin two distinct phases. Thefirst-phase is short lived, lasting for less than Sminutes,andis producedby the release
of insulin from the preformed secretory granules. The first phase is important in suppressing gluconeogenesis and in tackling postprandial hyperglycemia. This is
followed by a prolonged second phase, which lasts for 30 to 90 minutes, depending on the nature of the glucose load. This phaseis produced by thefresh synthesis of
insulin andrecruitmentofsecretory granules from the storage pool.

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18. Certificate Course in Evidence Based Diabetes Management (CCEBOM)
In type 2 diabetes, one of the earliest defects is loss of first phase insulin secretion.

Insulin exerts its action on the target cell by binding to insulin receptors on the cell membrane. The insulin receptor consists of A and B subunits. The A subunit
projects outside the cell surfaceand contains the insulin binding site. The Bsubunitis partly intracellular and can act asa tyrosine kinase when insulin bindsto the A
subunit. This leads to autophosphorylation of the receptor as well as a number of intracellular proteins, which include insulin receptor substrate (IRS), 1 and 2.The
phosphorylated proteins activate several second messengers, like phospholipids which mediate the various actions of insulin. There are two major intracellular
pathways of insulin action: the phosphatidylinositol 3- kinase (PI3K) pathway and the adapter protein (Grb-2-SOS) pathway. The PI3K pathway mediates the
metaboliceffects of insulin whereas the Grb-2-SOS pathway mediates themitogenic effects such as weight gain.

One of the most important actions of insulinis the synthesis and translocation of the glucose transporter (GLUT-4) to the cell membrane. This transporters found
chiefly in adipose tissue and skeletal muscle and is responsible for insulin dependent glucose uptake by these cells. Glucose uptake by other tissues is insulin-
independent and depends only onthe concentration gradient of glucose.

Other actions of insulin include promotion of glycogen synthesis, protein synthesis and lipogenesis and inhibition of glycogenolysi
andlipolysis.

gluconeogenesis, proteol

1.5.3.2 Counterregulatory Hormones

These are hormones whose chief effectis to antagonize the biochemical actions of insulin, The four medically important counterregulatory hormones are
+ Glucagon, from the a cells of the islets of Langerhans
+ Cortisol, from the adrenal cortex
* Catecholamines (particularly epinephrine, from theadrenal medulla andsympath:
* Growth hormone, from the anerior pituitary
All these hormones are important in the body's physiological defence against hypoglycemia, Glucagon and epinephrine are quick to act but their action is short
lived. On the other hand, growth hormone and cortisol are slow to act but long lasting. Glucagon acts mainly on the liver to stimulate glycogenolysis while cortisol
acts mainly in the peripheral tissues to stimulate gluconeogenesis, but all four hormones have some degree of action on both glycogenolysis and
gluconeogenesis.

icnerve endings)

In type 2 diabetes, in addition to deficient insulin activity, glucagon excess has also been noted and this may contribute to hyperglycemia. Drugs like incretin
analogs and DPP-4 inhibitors which suppress glucagon are therefore useful in type 2diabetes. As regards cortisol iatrogenic Cushing's syndrome is oneofthe most
commoncauses of secondary diabetes.

1.6 Pathophysiology of Type 2 Diabetes Mellitus (T2DM)

Type 2diabetesis the most common form of diabetesin the world, constituting more than 90% of all cases of diabetes. The etiopathogenesis of T2DM is complex
andhas beenthe subject of much study over the years. Asa resultof these studies, significant proportion of the riddle of causation of T2DMhas been unraveled.

The current understanding of the pathophysiology of T2DM is encapsulated in the latest classification of diabetes, which states that T2DMrepresentsa continuum.

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19. Module introduction to Diabetes Melitus

of clinical scenarios, ranging from severe insulin resistance (IR) with relative insulin deficiency to severe insulin deficiency with some degree of IR. Both IR and insulin
secretory defect are essential for T2DM to develop. An individual with even severe IR will not develop T2DM unless his insulin secretion drops below a critical
threshold. Conversely, an individual with absent insulin secretion but no IR willdevelop DM, but thisis, by definition, classified asT1DM or other rare forms of DM (like
MODY) ratherthanT2DM.

Itis not clear which comes first-IR or insulin secretory defect. All individuals become insulin-resistant to some extent as they grow older. However, most ofthem have
sufficient beta-cell reserve to overcome this IR andprevent the development of T2DM. It mightbe that individuals who developT2DM have a decreased B-cell reserve,
which renders them incapable of overcoming IR over a period of time.

IR can be inherited or acquired. The mostimportant corollary of IRs obesity, particularly abdominal obesity, which again can occur due to genetic or environmental
factors. There are certain genetic syndromes of severe IR, most of which are associated with DM. Use of certain drugs like corticosteroids can also produce IR and
thereby DM. Low birth weight has been postulated to predispose to IRlaterin life, although it isnot quite clear how. Reversible causes ofIR include physical inactivity
and chronic hyperglycemia (“glucotoxicity”) (Figure 5).

Figures

Insulin Resistance Vs. ß Cell Defect

Genetic Environmental | Genetic Environmental
Obesity Physical inactivity | ? Specific genes ff Glucotoxicity
Syndromes of Drug Lipotoxicity
severe IR birth weight Incretin defect
Low birth weight Inutero

malnutrition

\/ \/

Insulin resistance B cell defect

Increased insulin demand Reduced insulin supply
DIABETES

Resistance to insulin action can occur at the level ofthe insulin receptor or in the post-receptor pathways, Downregulation of the receptors as well as anti-insulin and
anti-insulin receptor antibodies have been implicated in the etiopathogenesis of T2DM. Iti of interest that resistance seems to develop only to the metabolic effects
ofinsulin (mediated bythe PI3K pathway) and not to the mitogenic effects (mediated by the Grb-2-SOS pathway).

20. Page 20

Certificate Course in Evidence Based Diabetes Management (CCEBOM)

Resistance to insulin action can occur at the level of the insulin receptor or in the post-receptor pathways. Downregulation of the receptors as well as anti-insulin
and anti-insulin receptor antibodies have been implicated in the etiopathogenesis of T2DM. Itis of interest that resistance seems to develop only to the metabolic.
effects ofinsulin (mediated by the PI3K pathway) and not to themitogenic effects (mediated bythe Grb-2-50S pathway).

‘Themajor contributor to B-cell dysfunction is genetic. The genes responsible for this impairmentin B-cellfunction remain unknown. TheB-cell defectis progressive
and can be detected even in individuals with impaired glucose tolerance (IGT) before they have developed DM. On an average, individuals would have lost at least.
50% of their beta-cell reserve by the time they develop DM. Environmental factors that contribute to ß cell dysfunction include chronic hyperglycemia
(glucotoxicity”), increased free fatty acids (“ipotoxicity”) alterations in the incretin axis (see below) and in utero malnutrition. Rather than a structural defect, a
functional defectseems tobe responsible forthe -cell dysfunctioninT2DM.

In addition to insulin, two other hormone systems deserve special mention in T2DM. The first of these, glucagon, is one of the physiological antagonists of insulin
(counter-regulatory hormone). This polypeptide hormone is secreted from the a cells ofthe pancreatic islets of Langerhans in response to a variety of stimuli, the
chief among which is a decrease in the blood glucose. It acts to raise the blood glucose levels chiefly by stimulating hepatic glycogenolysis and to an extent
gluconeogenesis. Its effect on extrahepatic tissues is negligible at physiologic concentrations. In normal individuals, high blood glucose levels lead to prompt
suppression of glucagon secretion. In type 2 diabetes, this feedback inhibition does not occur, leading toinappropriately high glucagon levels, which contributeto
hyperglycemia,

The second group of hormones is collectively referred to as“incretins”. These are hormones secreted from the intestinal epithelium in response to a carbohydrate
rich meal. They act on the pancreas and stimulate insulin secretion in a glucose-dependent manner, that is, they promote insulin release only if blood glucose is
h.

These are responsible for the “incretin effect” the ability of oral carbohydrate to stimulate insulin secretion to a greater extent than intravenous glucose. They also
hibit glucagon release from the a cell, slow gastric emptying and produce satiety and act on the central nervous system to reduce appetite and produce weight
loss. They havealso been shown to have a trophiceffecton $ cells in animal models, Thetwo important hormones in this groupare glucagon-like peptide-1 (GLP-1)
and glucose dependent insulinotrophic peptide (GIP;also known as gastric inhibitory peptide).These peptides have a short halflife since they aredegraded by the
enzyme dipeptidylpeptidase-4 (DPP-4) (Figure 6).T2DMis characterised by a bluntingofthe“incretin effect’.

Figure 6 Biological Effects of Incretins

Glycogen Gastric emptying
synthesis
Lipogenesis

Glucagon

21. Module introduction to Diabetes Melitus

Of late, in addition to the pathophysiologic defects mentioned above, other organs have also been postulated to playa rolein the pathogenesis of type 2 diabetes.
Thecomprehensive model incorporatingall these varying pathophysiologies has been termed the“ominous octet" (Figure 7).

Figure 7
Recent Concept in the Pathogenesis of Type 2 Diabetes

Ominous Octet

Hyperglycemia -®

se

nique annee Een te

1. 8 Cell impaired insulin secretion occurs early in the course of disease
2. Liver overproduction of glucose from liver in spite of hyperinsulinemia
3.. Skeletal muscle impaired insulin mediated glucose uptake
4. Adipose tissue FFA
AN Harmful adipocytokines
Gut diminished incretin effect
Cell‘ fasting plasma glucagon level and hypersensitivity of liver to glucagon
Kidney } renal glucose reabsorption.
Brain | in inhibitory response to appetite regulation “Cerebral insulin resistance”

1.6.1 Hyperglycemia and Other Metabolic Abnormalities in T2DM

‘The major sites of insulin action inthe body are the liver, skeletal muscleand adipose tissue. In a nutshell,insulin promotes utilization of glucose and energy storage in
tissuesas triglycerides in adipose tissueandas glycogen inthe liver. When IRdevelops, these processes either do not occur attheappropriaterates oroccur only at the
‘expense ofraised insulin levels. his compensatory hyperinsulinemiais one ofthe earliest biochemically detectable abnormalitiesin the process of developing T2DM.
Acanthosis nigricans is an important cutaneous marker of hyperinsulinemia. This is a hyperpigmented velvety lesion of the skin, found most commonly on the

roe?)

22. Certificate Course in Evidence Based Diabetes Management (CCEBOM)

posterior and lateral aspects of the neck, axillae and groins. It is most often met with in obese individuals with T2DM or prediabetes. Acanthosis nigricans is
postulated to be due tostimulation of epidermal ell growth byinsulin or insulin-like growth factor (GF). Acanthosis nigricansis often associated with skin tags.

Defective insulin action in the liverleads to inappropriate release of glucose, leading to fasting hyperglycemia, Usually, the hepatic glucose output is completely
suppressed after a meal, dueto the action of insulin. This suppression does not occurin individuals with IR, leading topostprandial hyperglycemiaas well. Also, the
production and release of verylow density lipoprotein (VLDL) stimulated, which contributes tohypertriglyceridemia. Individuals with hypertriglyceridemiatend
to have low levels of high-density lipoprotein (HDL) in their circulation, possibly because of exchange of triglycerides and cholesterol esters between HDL and
triglyceride-replete lipoproteins like VLDL, rendering HDL particles more susceptible to degradation. Also, the higher levels of VLDL lead to increased exchange of
cholesterol ester and triglyceride between VLDL and low density lipoprotein (LDL), increasing the triglyceride content of LOL and making them more susceptible
to degradation by hepatic lipase, leading to formation of small dense LDL particles (Figure 8).

Figure 8
Effects of Insulin Resistance on the Liver

Glucose ——————® Hyperglycemia
Hypertriglyceridemia

Low HDL Levels
Increased small dense LOL
ATHEROGENIC LIPID PROFILE

VLDL ‘Diabetic Dyslipidemia”

HDL - High Density Lipoprotein; LDL - Low Density Lipoprotein; VLDL - Very Low Density Lipoprotein

Thelipid profileinan individual withT2DMis therefore characterized by high triglyceride levels, low HDL cholesterol levels, and normalto high-normal levels of LOL
cholesterol, witha relative increasein the number of highly atherogenic small denseLDL particles. This’diabetic dyslipidemia’is one ofthe major factors underlying
the excessincidence ofatherosclerotic cardiovascular disease (ASCVD) in T2DM (Figure9).

Page 22

23. Module introduction to Diabetes Melitus

Figures
Pathogenesis of Diabetic Dyslipidemia

© TL Replete VLDL
A

LoL

A cect oti
mer
sil Denes LL SET wt nto ie

Defective insulin action in adipose tissue leads to excessive breakdown of triglycerides and formation of non-esterified fatty acids (NEFA). High levels of NEFA can
reduce insulin-stimulated glucose uptake by the tissues and can stimulate gluconeogenesis in the liver. Although lipolysis is increased, overproduction of ketone
bodies does not usually occur in T2DM because the insulin deficiency is not absolute; less insulin is required to prevent ketogenesis than to maintain glucose
homeostasis.

Insulin has also been postulated to have beneficial effects on platelet function, vascular integrity and the autonomic nervous system. IR can adversely affectall these,
probably accounting for some ofthe increased susceptibility to ASCVD seen inT2DM.
1.6.2 The Metabolic Syndrome and Type 2 Diabetes

It has long been recognized that various cardiometabolic risk factors like glucose intolerance, abdominal obesity, hypertension and abnormal ipids tend to cluster
together. This constellation of risk factors has been variously called the metabolic syndrome, syndrome X, insulin resistance syndrome and dysmetabolic syndrome.
The concept came to worldwide attention in 1988 when Gerald M. Reaven delivered the Banting Lecture on this topic, wherein he postulated that insulin resistance is
thebasicpathophysiology underlying this syndrome.

1.6.2.1 What is Metabolic Syndrome?

‘The metabolic syndrome is a constellation of cardiometabolic factors which if present in an individual increases his/her chances of atherosclerotic cardiovascular
disease,

Page 23

24. Certificate Course in Evidence Based Diabetes Management (CCEBOM)

Table 2. Harmonised Definition of Metabolic Syndrome

Obesity Waist circumference: Population and country specific”
Lipids’ Triglycerides: (mg/dl)
2150mg/dl

HDL (mg/dl): < 40 (men) < 50 (women)

Oron drug treatment for dyslipidemia
Blood Pressure 2130/85 mm Hg or on treatment for hypertension
Insulin Resistance — — Fasting glucose: > 100 mg/dl or on treatment for elevated glucose levels
DEFINITION OF MS Obesity and 2 or more other criteria

*Europeans:men > 94cm, women = 80cm; South Asians (Asian Indians): men 90cm, women 280 cm; Chinese:men 2 85 cm, women 280 cm; Japanese:menz 85 cm, women 2 90cm ;
South and central Americans: men > 90cm, women > 80cm; Sub-Saharan Africans:Men 2 94 cm, Women > 80 cm;Eastern Mediterranean and Middle East Arab) populations: men = 94
‘em, women =80cm.

“Triglycerides should be measuredina fasting blood sample; Totaland HDL cholesterol can bemeasuredeitherinthe fasting or postprandialstate
1.6.2.2 What risk factors are included in the definition of Metabolic Syndrome (MS)?

Various organizations and associations have given different definitions for Metabolic Syndrome (MS). These definitions vary in the risk factors to be included, the
cut-offlevels of these variables and the relative importance of each risk factor. This has led to immense confusion among researchers and students in thefield.

‘The Harmonised Definition (table 2) of MS aims to remove this confusion by providing unified diagnosticcriteriaforMS.

1.6.2.3 Why has the concept of Metabolic Syndrome become controversial?

Thedefinition of Metabolic Syndrome does not include some of the strongest risk factors for ASCVD like cigarette smoking and LDL cholesterol. Alsoitisfound that
there is poor agreement between the ASCVD risk calculated from well-validated scoring systems like the Framingham Risk Score and MS. Its also to be noted that
the diagnosis of MS does not add much information in a patient who has type 2 diabetes, who isalready at high risk for premature ASCVD. Such a patient should be
aggressively treated for ASCVD risk factors irrespective of whetherhehas MS ornot.

Probably it
tolerance- see Module 2). These people arelikely to benefit the most from early lifestyle modific

is more important to look for MS in individuals who have any of the syndromes of ‘pre-diabetes’ (impaired fasting glucose or impaired glucose
ions whichcan preventthe development of ASCVD in laterlife.

Page 8

25. Module introduction to Diabetes Melitus

Further Reading

1. SiNageshV,JoshiSR.Abriefhistoryofdiabetes.In:JoshiSR etlleds),RSSDITextbook ofDiabetes Melts Sthedn,).New Delhi Jaypee Brothers edicalPublishers,2020:pp.3-16.

2. International Diabetes Federation. Diabetes Atlas (10° edn), 2021. wivwictorg

3. Anjana RM, Deepa M, Pradeepa R etal. Prevalence of diabetes and prediabetes in 15 states of India: results from the ICMR-INDIAB population-based cross-sectional study. Lancet
Diabetes Endocrinol2017;5:585-596,

4. Unnikrishnan R, AnjanaRM, Mohan V Diabetes Melitus and its complications in India. Nat Rev Endocrinol 2016:12357-370.

5. Mohan V, Shah SN, Joshi SR et alon behalf of the DiabCare India Study Group. Current status of management, control, complications and psychosocial aspects of patients with diabetes
inindia:Results om theDiabCareIndia 2011 Study. Indian JEndocrinol Metab 201418:370-378.

6. Unnikrishnan R, Anjana RM, Deepa Metal for the ICMR-INDIAB Study Group. Glycemic control among individuals with self-reported diabetes in India- the ICMR-INDIAB Study. Diabetes
Technol Ther2014;16596-603.

7. Bhattacharyya A. Intermediary metabolism in diabetes mellitus. In: Joshi SR et al (eds), RSSDI Textbook of Diabetes Mellitus (Sth edn.). New Delhi, Jaypee Brothers Medical Publishers,
2020; pp.65-84.

8. DeFronzoRA, Banting Lecture-from thetriumvirateto the ominousoctet:anew paradigm forthe treatment oftype2 diabetes mellitus Diabetes 2009;58:773-795.

9. Alberti KGMM, Eckel RH, Grundy SM etal. Harmonizing the metabolic syndrome: jointinterim statement ofthe International Diabetes Federation Task Force on Epidemiology and
Prevention: National Heart Lung and Blood Institute; American Heart Association; World Heart Federation; Intemational Atherosclerosis Society and intemationalAssociation forthe
‘Study of Obesity. Circulation 2009;120:1640-1645,

Page 25 mo

27. DEPT A
DVD
u

X

> ee” ee
<a resentati

WI,
ID

Y

28. Presentations

Era, LE Da Mohans
KG) Bee pm rs)

‘CERTIFICATE COURSE IN EVIDENCE
BASED DIABETES MANAGEMENT 2
(ccesom)

Mode Hour Dahn Hal

Case Study 1

(A 52 year old man comes to you with blood glucose values of 198
mg/dl and 362 mg/dl in the fasting and postprandial stato
respectively. He is not known to have diabetes and was
discovered to have these values during a routine health check up.

1. What proportion of patients with di
have the condition?

2. What symptoms can alert one to the presence of diabetes?
How common are these symptoms?

3. What complications of diabetes can a patient have atthe time of
first diagnosis?

ibetes are unaware that they

Ste 3
Page 28

Learning Objectives

= To det abetos.

To am about somo of he Important milestones In the history o diabetes and
It management

To understand the magnitude ofthe problem of labs and the role ofthe
Primary care phyalcan in tacting Ht

To understand the basis of normal intermediary metabolism and ts
ormonal contol,

To lun about he pathogenesis and pathophysllogy of type 2 dabets and
speciale ts divers metabole consequences

sue 2
Case Study 2
‘An 85 year old man with diabetes of 42 years’ duration is evaluated.
You are pleased to find that ho has absolutely no evidence of any
chronic diabetes complications.

1. Can an individual with diabetes enjoy a normal lifespan?
2. Can diabetes complications be prevented totally?

29. Case Study 3

A 65 year old lady ls evaluated for diabetes and its

‘complications. She has diabetes of 16 years’ duration. She Is

found to have fasting and postprandial glucose values of 108

and 148 mg/dl respectively, and HbAtc of 6.8%. However, further

evaluation reveals the presence of proteinuria and moderate

‘nonproliferaive diabetic retinopathy.

1. Why should this patient with apparent good control of diabetes
develop complications?

2. What determines whether a patient develops diabetes
complications or not?

‘The patient concedes that her diabetes control had been poor forthe past
five fo six years and has only recently improved following initiation of
Insulin therapy. She also has uncontrolled hypertension.

—— ng

Definition of Diabetes Mellitus

The term diabetes melitus describes a metabolic cum vascular
syndrome of mullple etiology characterized by chronic
hyperglycemia with disturbances of fat and proton
metabolism resulting from defects in insulin secretion, insulin
action, or both leading to changes In both small blood vessels
(microangiopathy) and large blood vessels (macroangiopathy)

Module introduction to Diabetes Melitus

WHAT IS DIABETES?

MILESTONES
IN
DIABETES

30. First Report on Diabetes- 3500 Years Ago !

The Pancreas Takes Centre Stage

st Report on Diabetes In India
2% and 8° Century AD - Charaka and Sushruta

|

Diferendateddlabetes melts from diabetes Inlpidue
Recognised two types of diabetes
‘Kish: Lean Diabet (Type 1 abetos)
‘Stu: Obese Diabetic (ype 2 dlbetes)
Noted that diabetes runs In families
Describe polyuria and glycosuria (honey he urine)
Descried basis of tastment for diabetes
(phystal activity, dat te)
Noted that lan diabetes l dict to manage

ee EN

Discovery of Insulin

In November 1920, Frederick G. Banting, an othopede surgeon
‘employed aa later in physiology at Wostern Univers, Toronto,
was asked fo give a lecture onthe pancreas.

We preparing forthe lecture, his rest in pancreatic physiology
was inlod and he thought ofa vay to extract the panereatle
Secration that can reduce blood glucose without the pancreas
‘geting destroyed by pancreatic enzymes (by gating the pancreatic
‘uct, thereby causing aropty of exocrine pancreas).

Diabetes Lato pancreatic duct of dogs, Kewp dogs sive tl
ac! degenerate leaving lets; try To Isola the neral section | A

finos re gyconaia
‘Atv we sre by arg on 1,100

He presented his idea to James Macleod, Professor of
Physiology at Unversity o Toronto

ET

31. Discovery of Insulin
Maciod was ne impessd wih Banúng ide, bt agreed to

‘offer im the uso of ced ol lab and he sonic ofan
Sant

By a con toss, medical student Chavis. H Bas got the
‘chance 1 asia Banting

In their experiments, they induced diabetes in dogs by
removing the pancreas and ied to see whether gycosuria
‘ould be suppressed by administering Nid isolated rom the
lis of Langerhans of other heal dogs

July 30, 1921: First postive resus

Dog Marjorie: wes kept alive wit pancreatic extract
Injocton fr 70 days

Module introduction to Diabetes Melitus

Isletin: The extract named isletin was extracted in
pure form withthe technical guidance of Macleod and
the help of expert biochemist J.B. Collip

January 1922: a teenager wth diabetes named
Leonard Thompson was the first documented
person to receive insulin injection

Nobel Prize for Medicine In 1923

‘Awarded to Banting (who shared his award with Best)
and MacLeod (who shared his award with Colip)

Landmarks in Therapy of Diabetes

+ 1876- Hypoglycemic effect of salcyate noted
+ 1921 — Discovery of insulin

+ 1922-— First clinical use of Insulin

+ 1926 Insulin crystallisation techniques introduced

“+1926: The first biguanide derivative synthesized

+ 1930- Hypoglycemic effect of sulphonamides discovered
+ 1942- Prototype sulphonylurea synthesized

+ 1846 -NPH Insulin developed

+ 1955- The fist sulonylurea (carbutamido) introduced in clinical practice
+1956 - Lente insulin introduced

+ 1967 - Introduction of the first biguanide(phenformin)
+1963 - First promixed Insulin Introduced

Landmarks in Therapy of Diabetes

1978 - Subcutaneous Insulin infusion pump (Pickup, UK) introduced
982 - Recombinant human Insulin approved by USFDA

1998 ~The first alpha glucosidase inhibitor approved by USFDA
1998 - The first rapid acting Insulin analogue introduced

4997 = The fire thiszolidinedione introduced

2008 - The first long acting inulin analogue approved by USFDA
2008 - The first GLP-1 receptor agonist introduced

2006 - The fist DPP-4 Inhibitor Introduced

2013 ~The first SGLTZ inhibitor introduced

2014 The first long acting GLP! receptor agonist introduced
2019: The first oral GLP! receptor agonist approved by USFDA.

Paget

32. Diabetes

+ Tho leading cause of end-stage renal disease (ESRD)
+ The leading cause of non-traumatic lower limb amputation
+ One ofthe leading causes o preventable blindness
MAGNITUDE OF THE PROBLEM + Major risk factor for coronary artery disease and
(Type 2 Diabetes Mellitus) RARES

Worldwide, more than 537 milion adults suffer from diabetes;
{hs numbers aly fo go upto 7 milion by 245

betes Complications In India.

. The Numbers Epidemiology of Diabetes Mellitus
- Salient Features

+ T2DM comprises 85-95% of all cases of DM
+ Explosivo increase in prevalence of T2DM in developing countries
+ Steady increase in prevalence of T2DM in developed countries

+ TiDMalso increasing steadily in developed countries, but nota
major problem yet in developing countries (lack of data)

+Other forms of DM are rare

Milne (2019):

Page 32

33. T2DM in Developed Countries

+ Adisease of middle and old age
+ Associated with overweight and obesity
+ Worrying trend-increase in T2DM in children.

T2DM in India

+ Occurs a decade earlier than in the West
+ Occurs even in non-obese individuals

+ Occasionally seen in children also, although less commonly than
inthe West

‘+ More prone to develop cardiovascular disease
+ Some studies suggest lower risk of microvascular disease".

Highest Prevalence of Diabetes

2021

Module introduction to Diabetes Melitus

Top Five Countries: Diabetes Burden

2021
‘Country Porsons with DM (millions)

a i he Da a 20

WD
Rising Prevalence of Diabetes in India (1960s)
RURAL URBAN ET

ome paren

34. g Prevalence of Diabetes in India (2014)

RURAL ‘URBAN i Poa

The ICMR - INDIAB Study

+ Largest study on dabei in Inda

‘Studied ever state in naa using a systematic random sampling method to
‘obtain representative sample ofthe country

Total sample size = 124,000

‘The study has been completed and labels prevalence estimate for 15
states Union Terres have been published

side 26

Module Hire usi Dis Mel

Nearly 50% of People with Diabetes in India are
Undiagnosed
Data om te ICMRINDIAB Su

m

35. # National Programme for Prevention
and Control of Cancer, Diabetes,
Cardiovascular Diseases and Stroke
(NPCDCS)

‘An Initiative of Ministry of Health and Family
‘Welfare, Gov of India

Launchod with the objective of risk reduction fr prevention of non-
‘communicable diseases and ea diagnosis and management of cancer,
abetos, CVD and stroke

Plot phase launched In 10 distrits of 10 st

on 4% January 2008

"The main programme was approved by the Union Cabinet Committeo
in July 2010

ROLE OF THE
PRIMARY CARE PHYSICIAN

Module introduction to Diabetes Melitus

National Programme for Prevention and Control of Cancer,
Diabetes, Cardiovascular Diseases and Stroke (NPCDCS)

Has covered al sit ofa state UT in India by the end of 12 5-year plan

aa

Diabetes is Too Large a Problem for the
Government to Tackle on its Own!

i osteo
mme,
I ‘burgeoning epidemic

Hence it ie important that every general practitioner be familiar
with the basics of diabetes management

Pe 77

Page 35

36. The Epidemic is Spreading...

Nearly 20% of Adult Patients in a General Medical
OPD Will Have Diabetes...

But more than half of those
patients are unaware that they
have the disorder!

“The primary care physician has a unique opportunity to identify and
‘reat these cases at the caries! possible stage

In all these places, the primary
care physician has a major role
in identifying and managing
diabetes and making prompt
referral if any person with
diabetes has any complications

Status of Diabetes Awareness In India

Astato of blissful ignorance!

+ Only around 43% of individuals have ever heard of diabetes.
+ 50% do not know that diabetes can lead to organ complications
+ More than 80% do not know the risk factor for diabetes

+ 50% do not know that diabetes can be prevented

‘The primary care physician has a major ol in educating hi

nts and hai
reves abut bats, o that they sek detection and care

me

37. Status of Diabetes Control In India

A case of too litle being done too late?
+ Ont around 20.80% of patins have HAC <7%

+ No consensus on glycemic targets and guidlines among doctora
+ Management o pis and blood pressure is suboptimal

+ More than 50% of paints not informed about gyeomic targets

‘The situation can only be improved by training the primary caro
physicians who treat most ofthe diabetes patients In this country

This Course...

‘Aims at creating a cadre of trained primary care physicians to
tackle the diabetes epidemic in india

Module introduction to Diabetes Melitus

ary Care Physician

Ideal situated to provide quality
diabeles care tothe patient on
‘account of.

+ Acceptability

+ Availability

+ Affordability

‘Atrained primary care physician is the
‘best bot to tackle the diabetes
‘epidemic inthe Indian scenario

NORMAL GLUCOSE METABOLISM

Page —

38. Dietary Carbohydrates

+ Main sources of energy
= Include simple sugars tke glucose, sucrose and lactose and Carbohydrate

‘complex carbohydrates Ike starch and glycogen
+ Complex carbohydrates have to be broken down to Salivary amylase
monosaccharides i they are to be absorbed. Pancroaii amylove
Oligo- and disaccharides
Intestinal Disaccharidasos.
= (rush border enzymes)

Monosaccharides —+ ABSORBED

Module Hits ol

Fate of Glucose- Postprandial State
+ Entry of glucose into skeletal muscle cells is insulin-dependent;
In other col, uptake takes place along the concentration cono
gradient
+ Onco inside the cel, glucose is converted (activated) to glucose
-$- phosphate by hexokinase or glucokinase enzyme Se
+ All cells can convert glucose-6- phosphate into pyruvate +
(glycolysis) CAN
= Pyruvate can be converted to Acatyl CoA, which can be used in
the synthesis of fatty acids or completely broken down to CO;
and H,O (TCA cycle) wth release of largo quanties of ATP.
{energy (rainy in brain) paths owls
+ Incontracting muscle, pyruvate s converted to lactato
Inver and skeletal muscle, glucose-6-phosphate is converted to T
cogen (glycogenesis) LR CA Am
se 43 u me 4

Fate of Glucose in the Cell

39. | Adaptation to Fasting - Energy Stores
Olsen bg mtb lr neurone
= ar cnna tan pepe meo han ns
+ tne a mecarla ented Bl a mar mao cs

glucose level wii a narow range even ar prolongada oven fi
means tha otr guey have fo make de wih alert fos ee fay

‘oie and tons boden)

Source of nr rg et nce:
cogen

Mila 25% a sa mc (15)

ute ho nt

Ft be han por
‘yee

peor soc ody tr ou tg

tas rr prompt

can dom nd ge!

in as

Cori Cycle

+ Te Costes a means by which muscle icon canbe uz o maintain
ste va re inh toi mcs oth sl os se

+ halo hos In proving lcosoto he musch a ul ing contacto

Module introduction to Diabetes Melitus

Adaptation To Fasting

First 26 hours Giycogenoyas
cogen fr ver & mus)

[Seas
ee

ll

4 lo

Adaptation to Fasting

+ ter 24 hours - Gluconcogenosis
+ Production of glucose from non-carbohydrate precursors
+ Usual substrates are lactate, glucogenic amino acids

(@lanine),propionyt CoA and glycerol part of fat

‘The main sites ae liver and renal cortex

40. Hormone Effects- Fed State

“The only hormone Involved is INSULIN
Insuln

+ Promotes gycolsis

+ Promotes gycogenssis.

"Prien crane (mtm anton tum ty aci sd
a

+ Promotes protein synthesis

= Iii gluconeogenesis, glycogenolsi, proteolysis and Ipolsis

Incretins: Mechanism of Action

“These are hormones derived from the gut epithelium hat bind to
surface receptors on target calls o broadly affect metabolic
physiology

+ Enhance insulin production, secretion, and responsiveness.

Increase islet B-cll mass, slow gastric emptying, suppress appetite
Inhibit glucagon secretion and suppress hepatic glucose production

"The naturally occurring Incretns aro
+ GLP-t. Gcagorike peptide-+
+ GIP. Gucose dependent Insunatropi Peptide

st
Page

Hormone Effects- Fasting State

“The frst hormone response to fasting Involves suppression of
insulin secretion

‘This is followed by increased secretion of countr-regulatory
hormones.

Glucagon and epinephrine are quicker in onset but short lasting
Growth hormone and cortisol have slower but persistent effects

+ Net result ofthese hormonal changes is to increase endogenous,
glucose production by means of lycogenolysis and
Qluconeogenesis as well as increased production of free fatty acids
and ketone bodies by lipolysis.

The Incretin Effect Demonstrates the Response

to Oral vs. IV Glucose

A Pr Etre

41. Role of Incretins in Glucose Homeostasis

Ingestion of food

| Release of gut
omonss
tract Inert
‘ative

a

Glucose dependent
Glucagon from

eels
Co

Module introduction to Diabetes Melitus

PHYSIOLOGY OF INSULIN

Structure of Insulin

Insulin isa polypeptide hormone consisting of two chains-
“he chain” wth 24 amino acido
Beba” with 30 amino acide

Insulin is Secreted from the B-Cells of the
Pancreatic Islets of Langerhans

GS —

42. Insulin Biosynthesis

mer = se nu
Amer : ;
(Bo co

vee © oy

Glucose- stimulated Insulin Secretion
1. Entry of glucose into call
(ia GLUT2)
2. Acivaïon of glucose by

enzyme
3. Metabo of glucose with

4. Binding of ATP to K-ATP

Module ins ocn o is Mal

Regulation of Insulin Release

Inititors of Insuli Secretion
Gucose, certain amino cid (wucine, eine,
lino), fat acids

Potentiators of Insulin Secretion
(Amplty insulin release only in the presence

Inhibitors of Insulin Secretion

Glucose- stimulated Insulin Secretion

Insulin Secretion Following
‘a Glucose Load is Typically 8
Biphasic

The first phase lasts only fora
few minutes and is due to
release of insulin from granules
located close to call surface

‘The second phase lasts as long
as the high glucose stimulus
persists and is due to release of
freshly synthesised insulin as.
‘well 8 from granules moblised
from the interior ofthe cel

—— a

43. Insulin Action

‘The main Insulin sensitive tissues are Ive, skeletal muscle and

adipose tissue
In all these issues, insulin exerts its action by binding to the Insulin.
receptor on tha cell surface

RN

Subsequent events (downstream events) vary depending on the
‘issue involved and are responsible forthe diferontial actions of
Insulin on various tHesues

Insulin Action

In adipose tissue, Insulin...

+ Increases the avallabiliy of free fatty acids (FFA) and glycerol by
stimulating Ipoprotein lipase

+ Stimulates lipogenesis

+ Inhibits ipolysis by inhibiting hormone sensitivo lipase

Module introduction to Diabetes Melitus

Insulin Action
In the liver, Insulin...
+ Reduces hepatic glucose output
Glucose uptake into the liver is.
not dependent on insulin,

Insulin Action

In skolotal muscle, insu

Increases glucose uptake by stimulating
translocation of GLUTA from intracellular
sitos to the surface ofthe cell

Glucose uptake into skeletal muscle Is.
dependent on insulin,

Page —

44. Differential Action of Insulin is Mediated by
Post-receptor Events

Grb-2 $08 (MAP Kinaso)
mediated pathways,

Case Study 4

A 56 year old lady is detected to have diabetes.
‘She weighs 88 kg and ls 162 cm tall.

She also has hypertension and her serum cholesterol ls 282
mg.

On examination, you find that she has acanthosis nigricans on
the nape of her neck.

Wat is the main pathophysiology of diabetes in this lady?
What wil be the main treatment goals In hor case?

PATHOGENESIS OF TYPE 2 DIABETES

Case Study 5

/A45 year old man is detected to have diabetes.
He weighs 68 kg and ls 177 cm tall.

He gives a history of increased thirst and frequency of urination
for the last three weeks, and has lost 3kg in weight over the
same time period.

He does not have acanthosis nigricans or skin tags.

What is the main pathophysiology of diabetes in his case?

45. Main Defects in T2DM -
The Conventional View (“The Triumvirate”)

= |
era
EZ. BR eS

‘The relative contributions of these factors may vary In each case of T20M

Physical ‘Giucotoxilty
inactivity Lpotoxicty

Drugs In utero detects

Low birth weight Incrtin detecta

Module introduction to Diabetes Melitus

Development and Progression of Type 2 Diabetes*

Definition of Insulin Resistance

A state in which a normal amount of insulin produces a
‘sub-normal response

46. a RUN
y

—
PnosphatisyInoshol (PI) 10-2508 (MAP Kinase)
lated pathways mecita pathways

Liver, skeletal muscle and adipose

tissue (afferent downstream
vents at each site)

‘Action receptor emer Metabo facts Fiitogericetects |

antibodies S

Side 74

Major Sites of Insulin Resistance Major Sites of Insulin Resistance
Liver
* Accelerated gluconoogenesis Skeletal Muscle
+ Accelerated glycogenolysis. + Reduced glycogen synthesis.
ty ame hepatic ghacome = Reduced uptake of glucose after a meal
si PP” + Increased deposition of triglycerides.
socrotion of TG-rich VLOL.

Page a6

47. Module introduction to Diabetes Melitus

Major Sites of Insulin Resistance
) Conditions Producing Insulin Resistance

LTE ALA Adipose Tissue .
Bug Eos a
2 ee a of free fatty acids + Overweight and obesity
me bg + Abnormal balance of A
¡Gar a. au Endocrinopathies (Cushing syndrome, acromegaly)
> Ir « Reduced adiponectin levels + Drugs (Steroids)
ge + High levels of leptin, resistin
eens

Phases of Insulin Resistance

Common Clinical Correlates of Insulin Resistance
First Phase
+ Normal plasma glucose due to compensatory increase in insulin + Overweight or obesity

en + Palyeystic ovarian syndrome.

Second Phase + Nonalcoholic fatylver disease (NAFLD)

+ Worsening of insulin resistance leading to post prandial hyperglycemia

spite elevated insulin secretion + Diabetes or dysghycemia
Third Phase + Skin changes (Acanthosis niricans, skin tags)
+ Insulin resistance remains constant; Decine in beta cel function oH jon

producing fasting hyperglycemia =

48. Clinical Findings Associated with Insulin How to Measure Insulin Resistance
Resistance oo . snemie ie dump
However this technique is fut perform in routine cn

‘Therefore, simpler calculated indices have been Introduced to measure
Insulin resistance In ih clinical setting,

+ Homeostasis Model Assessment (HOMA)
+ Quantitative insulin sensitivity check index (QUICK)

How To Measure Insulin Resistance Defects in B-cell Function In T2DM
HOMAIR

+ Defective frat phase nen secretion with delayed hypriulnemia 2 hour star
‘homes
(Fasting Glucose mg/dl X Fasting insulin

2 pUimyaos =

glucose ls measured In mmol, use 22.5 Instead of 405

‘quick w + Normal
= ‘(log fasting Insulin + log fasting glucose) e ad
However, tn normal ranges fr ose values vary widely rom population de

to Population (eg Inthe urban Chennai population, a value of HOMAIR

more than 2.58 has boon considered suggestive of") e

“Thos indice ar therfore useful or comparing insulin resistanco

between individuals but not or determining whether a particular person is »

insulin resistant or not E

“These measurements are not essential In daly cnica! practice E à m

Tee ony

49. Defects in B-cell Function in T2DM

+ Decrease or absence in pulsatliy of insulin secretion
+ Impaired reactivity of beta cel to glucose and other
secretagogues

+ High amounts of proinsulin and insulin split products in B-cell
secretion

+ Abnormal gene expression and transcription
+ Brcell apoptosis

Which Comes First- Insulin Resistance or B-cell
Defect?
‘Awa chicken-and-oggsuston!

Module introduction to Diabetes Melitus

Glucotoxicity
Diminution o insulin secretion following prolonged exposure to high
ovals of blood glucose

Chronic hyperglycemia depletes the insulin secretory granules from the
‘Balls, thereby reducing the amount of insulin available for secretion,

‘Lowering of blood glucose permits regranlation of el, and recovery
final response
Lipotoxicity

High levels of circulating free fatty acids can Inhibit conversion of
proinsulin to insulin, leading to defective Insulin secretory response

Other Hormonal Defects in T2DM

+ Hyporglucagonemia
- Blunting of Increin effect

+ Some investigators have reported lower levels of GLP-1 in T2DM,
but this has not been confirmed by recent studies.

50. Decreased Insulin, Elevated Glucagon and
Hyperglycemia in Type 2 Diabetes

=>
cto À Lea
mes m. A.

Incretin effects.
bluntadin type 2
diabetes

Genes and Type 2 Diabetes

+ Type 2 diabetes Is genetically heterogeneous
+ Common forms of type 2 diabetes are polygenic

+ Strong gene - gone interaction and gone environment
Interaction plays a major role In development of diabetes

* Therefore a proper family history should be elicited

Recent Concept in the Pathogenesis of T2DM

From the Triumvirate to the Ominous Octet,

| Ominous ote

Modal a bre a

Environmental Factors

+ Sedentary le style

+ Consumption of diets high in fat and calories
+ Lack of physical activity

+ Psychosocial factors (stress, depression)
All these are risk factors for diabetes.

51. Module introduction to Diabetes Melitus

Gene - Environment Interaction in Diabetes

=e a
ttre an
METABOLIC ABNORMALITIES

IN T2DM

Type 2 Diabetes: Major Metabolic Defects

Peripheral insulin
resistance in muscle

and fat

rra ie
a ¿Pucca leon
Yale ution THE METABOLIC SYNDROME

Relative insulin
denciency

Hepatic insulin Pino predation
resistance Tone ouput
Veces on

52. The Insulin Resistance Syndrome
(‘Metabolic Syndrome”)

Gerald M. Reaven postulated the
‘common etiology of insulin
resistance for “Syndrome X" at the
‘Banting Lecture in 1988, gaining
worldwide attention

Definition

"Metabolic Syndrome" describes a cluster of CVD
risk factors and metabolic alterations associated
with excess body fat / weight

Also known as
+ Syndrome x

2 Insul resistance syndrome
+ Motaboli syndrome

+ Beer-belly syndrome

+ Dysmetabolic syndrome

+ Roaven's syndrome

Harmonised Definition of Metabolic Syndrome

Guay ae
EYE sonate

cmenncar course mn EvDENCE :@

BASED DIABETES MANAGEMENT LT

emo :
al N

Welser
Biaseres

53. Module introduction to Diabetes Melitus

How Will You Diagnose Diabetes ?

Syearoid f2yearold 1Syoarcld 20 year old

by Lal q pa Wi you do a glucose

FPG 208 FPG 196 FPG20S FPG2M tolerance test

PPPGS2 PPPG320 PPPGS2 PPPGIS Ora fasting blood glucose
mue HbAtc9.8% HbAfc99% HbAc 10.2% {Or a urine sugar test |

“These are four young patients with similarly high plasma glucose loves.
Do they ll have the same type of diabetes?
How can you differentiate the types of diabetes?

What Is The Test ? Learn How To Monitor A Diabetes Patient

Fret tt nce in Oncein Annually
remonte simon

How is itdone and

what is It used for?

‘Learn about clinical and laboratory evaluation of a diabetes patient ?
.
1 "
=

54. Learn the answers to these questions

and much more.

In Module 2

Presentation and Initial Evaluation of
‘Type 2 Diabetes

Page s4

55. NOTES:

56. NOTES:

58. Published by:

Public Health Foundation o India
Program Secretariat CCESDM

Plot Ne 47, Sector 4, Institutional Area, Grugram-122002, Haryana, nda
Tel [phone] Ext: 4509

Emalt diabetesrningephforg | Web: wwwccebdmor, wwwphtorg