Insulin Resistance

Dr Lavina Jain
Regional Medical Advisor
Abbott Healthcare
Diabetes Prevalence:
Global
• As per IDF 2021 atlas, 537 million
people worldwide have diabetes.

• This represents 10.5 % of the

world’s population in this age
group.

IDF atlas. 10th Edn. 2021.

 Diabetes Prevalence: India
• India ranks 2nd with an estimated 74.2
million (7.4 crore) adults aged 20–79
years are currently living with
diabetes

• The number is expected to reach 124

million (12.4 crore) by 2045.

• This represents 10.4% of the India’s

population in this age group.

IDF atlas. 10th Edn. 2021.

 Diabetes in India
• An exponential increase in T2DM prevalence in India in the last 30 years has played a major role in
contributing to the increased burden of diabetes in young age-group.

• T2DM onset in Indians is nearly two decades earlier than in the west.

•  T2DM in Indian patients is characterized by

 Lower BMI
 Increased body fat
 Increased clinical and biochemical measures of insulin resistance and systemic inflammation
 Coupled with one of the highest global rates of pre-diabetes progression to T2DM (14-18, 6 and 2.5% p.a. in
India, Finland and USA, respectively), highlighting a more aggressive diabetes phenotype in Indians

Dutta D, Ghosh S. Young-onset diabetes: An Indian perspective. The Indian journal of medical research. 2019 Apr;149(4):441.
Young population is most affected..

• Early-onset type 2 diabetes appears to be a Relative risk of myocardial infarction with

more aggressive disease from a diabetes
cardiovascular standpoint.
• Adults with early-onset type 2 diabetes
were also 20% more likely to develop
microalbuminuria than those with usual-
onset type 2 diabetes
• Young adults with diabetes and especially
young women have a 14-fold increased
risk of MI compared to patients with usual
onset T2DM

Hillier TA, Pedula KL. Complications in young adults with early-onset type 2 diabetes: losing the relative protection of youth. Diabetes care. 2003 Nov 1;26(11):2999-3005.
 Escalation of Prevalence of Diabetes in India
1. Increased Insulin resistance
• Higher prevalence of Insulin Resistance in Indians (13%) as
compared to other ethnic groups groups [Mexicans:3.0%,
Japanese:1.6%] 1-3

2. Strong Genetic Factors in Indians:

• Certain genes predispose Indians to diabetes
• While other genes (for example Pro 12 Ala polymorphism of
PPAR gamma gene) which afford protection against diabetes and
insulin resistance to Caucasians, do not appear to protect Indians. 4

3. Role of Environmental Factors 1

• Epidemiological transition
• Prevalence of insulin resistance across
Physical inactivity
ethnic groups
• Dietary alterations
• Obesity
1. Mohan V. J Assoc Physicians India. 2004 Jun;52:468-74.
2. Villalpando GC, et al. Arch Med Res 1995;26:Spec No.S9- S15.
3. Imamura M, et al. Clin Exp Pharmacol Physiol (Suppl) 1995;1: S30-S31
4. Radha V, et al. Indian J Med Res 125, March 2007, pp 259-274.
Glycemic control is poor in Indian diabetic patients,
with a mean HbA1c of 8.9 ± 2.1%1
Achieving target
glycemic goals..
Only 19.7% of the Indian diabetic population achieve
the HbA1c target of <7%1

47% of patients do not achieve the glycemic targets

even after dual or triple drug therapy2

1. Mohan V et al. Indian journal of endocrinology and metabolism. 2014 May;18(3):370.

2. Paneerselvam A et al. British Journal of Medical and Health Research 2016.

Reasons for uncontrolled glycemic control..

1.Unhealthy eating habits

Factors linked with 2.Physical inactivity
uncontrolled glycaemia
in T2D patients include 3.Nonadherence to medication
4.Lack of regular blood glucose monitoring

• Pamungkas RA et al. Behavioral Sciences. 2017 Sep 15;7(3):62.

 Type 2 Diabetes

• The most prevalent form of diabetes (accounts up to 90-95%

of all the forms of diabetes)

Old view: predominantly insulin resistance and relative

(rather than absolute) insulin deficiency.
ADA Position Statement. Diabetes Care 2009; 31(S1): S55-S60

Current view: progressive insulin secretory defect on

the background of insulin resistance.
ADA Position Statement. Diabetes Care 2014;
37(S1): S14-S78
Glucose influx and outflow

• Any rise in glycaemia is the net result of glucose influx exceeding glucose
outflow from the plasma compartment.
• In the fasting state, hyperglycemia is directly related to increased hepatic
glucose production.
• In the postprandial state, further glucose excursions result from the
combination of insufficient suppression of this glucose output and defective
insulin stimulation of glucose disposal in target tissues.
The hormonal regulation of glucose metabolism

Hypoglycaemic Hyperglycaemic
hormone hormones

14
 Effects of insulin on glucose influx/outflow

Increases glycogen
synthesis
Decreases glycogenolysis

Inhibits gluconeogenesis

Increases the uptake of

glucose
by stimulating the exposure of

GLUT4 in cell membrane

Kahn R, et al. Joslin’s Diabetes Mellitus,
Stimulates glycolysis 2005. Dimitriadis G, et al. Diabetes Res Clin Pract 2011; 93
(S1):S52-S59
 Etiology of type 2 diabetes

• Interaction between genes and environment can

lead to obesity and insulin resistance.

• Genetically susceptible β- cells are unable

to compensate the increased secretory demand,
resulting in type 2 diabetes.

Adapted from Kahn, Hull, et al

2006
Insulin Resistance- Definition
• The condition in which normal amounts of insulin are inadequate to produce a
normal insulin response from fat, muscle and liver cells.
Etiology of IR
• Genetic factor
• Medication- steroid, glucosamine etc
• Conditions- Obesity, metabolic syndrome, pregnancy, infection or severe
illness, stress etc.
 Theβ-cell in type 2 diabetes: function

At the time of diagnosis patients with T2D already show

an impaired β-cell function, that progressively decreases during
the disease

100
-cell function (%, HOMA) Diabetes diagnosis
80

60

40

20

0
–12 –10 –8 –6 –4 –2 0 2 4 6 8
Years to diagnosis
HOMA: homeostasis model assessment
Adapted from: Lebovitz, Diabetes Reviews 1999;7:139–53
17
(data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58)
 The β-cell in type 2 diabetes: mass

2,5
-cell volume (%)

2 -50%

1,
5 -
63%
1

0,5
0
NGT IFG T2D NGT T2D LADA

Obese Lean
18
Butler AE et al. Diabetes 2003; Leslie RD e Pozzilli P, J Clin Endocrinol Metab 2006; Deng S et al.
The loss of β-cell mass and function results in the
progressive insulin secretory defect…

800

600
(pmol/min)
normal
secretion

400 type 2
Insulin

diabetes

200

Breakfast Lunch DInner

0
6.00 10.00 14.00 18.00 22.00 2.00 6.00
Hours
19 Polonsky KS et al. N Engl J Med,
1988
 …on the background of insulin
resistance
• Increased insulin resistance in muscle, liver and adipose
tissue causes hepatic glucose overproduction, impaired glucose
uptake from muscles and increased plasma levels of FFA

IR: Insulin
Resistance PG:
Plasma glucose IS:
Insulin Secretion

Taylor R Diabetologia 2008; 51: 1781-

 The twin vicious cycle of insulin resistance leading
to T2D

Plasm
a
glucose

21
Taylor R Diabetologia 2008; 51: 1781-
Insulin Resistance- Pathophysiology
 Obesity and insulin resistance

22
Obesity is associated with a variety of serious (and
expensive) medical conditions

• High blood pressure

• Atherogenic dyslipidemia
 low HDL, hi TG, increased small dense LDL particles, slow
clearance of TG from the blood
• Vascular disease
 Coronary artery disease, carotid artery disease, peripheral vascular
disease
• Glucose intolerance and type 2 diabetes
• Clotting problems
Obesity is associated with a variety of serious (and
expensive) medical conditions
• Nonalcoholic fatty liver disease
• Sleep apnea
• Pro-inflammatory state
• Certain forms of cancer
• Polycystic ovary syndrome
• Gout
Obesity-related medical conditions have a common
denominator:

Insulin resistance and compensatory

hyperinsulinemia
Key point:

Not all obese people are insulin resistant

or at risk for these disorders and not
everyone with these disorders is
overweight
Some type 2 diabetics are normal weight

“Once you're a diabetic, you're

pretty much a diabetic," says
Berry. "I have adult onset
diabetes. I was diagnosed when
I passed out one day. I've
gotten my diabetes to a really
manageable place. So I don't
have really any complications
due to it, but I still have to deal
with it and check my blood
many times a day."
USA Today 10/21/02
And some obese people are insulin
sensitive

“….substantial numbers of
overweight/obese individuals remain
insulin-sensitive, and not all insulin-
resistant persons are obese.”
Gerald Reaven, MD

Diab Vasc Dis Res 2005 Oct;2(3):105-12

Insulin resistance and obesity
• ~ 75% of individuals in the most insulin-resistant tertile are
overweight/obese
 That means 25% of insulin resistant individuals are not overweight/obese

• 30% of those in the most insulin-sensitive tertile are

overweight/obese but are at low risk for IRS
• Metabolic benefit and decrease in risk of CVD following weight
loss occurs primarily in those overweight/obese individuals that
are also insulin resistant

Diab Vasc Dis Res 2005 Oct;2(3):105-12

 Metabolic Syndrome is the term used for
clusters of CVD risk factors

• Atherogenic dyslipidemia
• Elevated blood pressure
• Elevated glucose
• Central obesity
• Increased prothrombotic factors
• Increased proinflammatory factors
Criteria for diagnosis of Metabolic Syndrome

NCEP ATP III* WHO*** ACE/AACE

Overweight/ Waist circumference: Waist:Hip >0.9 (men) BMI >25
obesity >40” (men) 0.85 (women) or BMI
>35” (women) >30 kg/m2

Trigl > 150 mg/dl same same

HDL < 40 mg/dl (men <35 mg/dl (men) Same as ATP III
< 50 mg/dl (women) <39 mg/dl (women)

BP >130/>85 mmHg > 140/90 > 130/85

IFG >100 mg/dl** > 110 or IGT or glu >110 and 126 mg/dl
uptake < lowest quartile or 2 hr p glucose
challenge >140
mg/dl;
Microalb N/A > 20 microg/min or
alb:creat > 30mg/g
*3 out of 5 needed to make dx **Original criteria defined IFG as >110 mg/dl ***Must have IGT, IFG, IR, or DM plus 2 of the
other 4
Insulin Resistance Syndrome vs Metabolic
Syndrome

• Insulin resistance syndrome (the endocrinologists’ view of the

world)
 Unifying pathophysiology: insulin resistance & compensatory hyperinsulinemia
 Loosens the link with obesity

• Metabolic syndrome (the cardiologists’ view of the world)

 Term widely used
 Links clusters of conditions with risk of CVD
 Obesity is often an defining element of the syndrome
Insulin resistance and compensatory
hyperinsulinemia
• Individuals vary in their sensitivity to insulin
• Insulin resistance leads to increases in insulin secretion in order to
maintain normal blood glucose
Insulin resistance and compensatory
hyperinsulinemia

• Compensatory hyperinsulinemia is responsible for most, if not

all, of the abnormalities and clinical syndromes that constitute
IRS/MetS*
 Syndrome X, insulin resistance syndrome, metabolic syndrome

• When the pancreas cannot keep up with demand, insulin

insufficiency occurs (glucose intolerance, type 2 diabetes)

Diab Vasc Dis Res, 2005 Oct;2(3):105-12

Continuum of metabolic derangements related to insulin
resistance
 Diabetes is a late manifestation

Normal Weight gain,

metabolism, increased insulin
normal weight, resistance Type 2 Diabetes*
genetic and compensatory
predisposition hyperinsulinemia

*70-80% meet criteria for metabolic syndrome, all have insulin resistance
We need to stop thinking about type 2
diabetes in a binary mode

• Increased cardiovascular and stroke risk begin before the onset of

clinical diabetes
• Progression to diabetes can be slowed or, perhaps, prevented
• Insulin resistance should be recognized and addressed before
irreversible damage occurs
Measurement of Insulin Resistance
• Hyperinsulinemic euglycemic clamp
• Insulin Tolerance Test
• Minimal Model Test
• Homeostatic Model Test
• Quantitative insulin sensitivity check index (QUICKI)
Who is at risk for IR
• Overweight (BMI>25)
• A man with a waist > 40 inches or a woman with a waist > 35 inches
• > 40 years of age
• Latino, African-American, Native American or Asian American
• Have a family history of type 2 diabetes
• Have had gestational diabetes
• Have high BP, high blood TG, low HDL-C
Treatment of IR
• Weight reduction
• Exercise, and
• Dietary modifications
Dietary Components Which May Affect Insulin Resistance
↓ IR ↑ IR
• Saturated fat
• Whole grains
• Salt (deficiency or
• Fruits and vegetables excess)
• Alcohol (>30g/day)
• Low fat dairy products
• Magnesium
• Calcium
• Dietary fiber
• Omega-3 fatty acids
• Low GI foods
 Glycemic Index

Foods with similar

carbohydrate
content can affect
blood glucose
levels differently

Ludwig, D. S. JAMA 2002;287:2414-2423.

• Potato
• Instant oatmeal
• White bread
• Watermelon

• Basmati rice
• Stoneground whole wheat bread
• Raisins
• Pineapple

• Kidney beans
• Chocolate ice cream
• Oatmeal made with steel-cut oats
• Spaghetti, al dente
Glycemic Index and Diabetes
High Glycemic Index Meal

Postprandial Hyperglycemia ↑ FFA

Hyperinsulinemia Glucotoxicity Lipotoxicity

Relative INSULIN
Reactive RESISTANCE
Hypoglycemia BETA CELL FAILURE
Counterregulatory
Hormones
The Low Glycemic Index Diet:
Epidemiologic Studies
In some but not all studies, low GI diets are associated with:
 Increased insulin sensitivity
 Reduced adiposity
 Reduced risk of metabolic syndrome
 Reduced risk of type 2 diabetes
The Low Glycemic Index Diet:
Clinical Trials
• Low GI diets:

 Reduce postprandial glucose levels in normal individuals and people with diabetes
(Ludwig, JAMA, 2002)
 Produce modest improvements in HbA1c in patients with diabetes (Brand-Miller,
Diabetes Care, 2003)
 May or may not affect insulin sensitivity (improvements noted in 2 of 7 studies)
The Low Glycemic Index Diet:
Clinical Trials
Low GI diets:

 May be beneficial for weight management, particularly in individuals with

features of the metabolic syndrome (Pittas, Diabetes Care, 2005)
 May reduce LDL cholesterol and TG and increase HDL (Luscombe, EJCN,
1999 and Pereira, JAMA, 2004)
 May reduce inflammatory markers such as C-reactive protein (Pereira, JAMA,
2004) and IL-6 (Kallio, AJCN, 2008)
 May increase antioxidant capacity (Botero, Obesity, 2009)
Insulin Resistance at a glance
• Insulin resistance is a condition in which the cells of the body
become immune to the hormone Insulin
• Insulin Resistance may be a part of the metabolic syndrome, and
associated with the development of heart disease
• Insulin Resistance precedes the development of type 2 diabetes
• Insulin resistance is associated with other medical conditions
including fatty liver, atherosclerosis, acanthosis nigricans, skin
tags and reproductive abnormalities in women.
 Contd…
• Individuals are more likely to have insulin resistance if they have
any of the associated medical conditions listed above.
• They are also more likely to be insulin resistant if they are obese
or are Latino, African-American, Native American, and Asian-
American.
• While there is a genetic component, insulin resistance can be
managed with diet, exercise and medication.