understanding diabetes and insulin resistance syndromes dr. amel arnaout

Understanding Diabetes and Insulin Resistance Syndromes

Dr. Amel Arnaout

Objectives• 3676 Describe the different types of diabetes mellitus and their distinguishing

characteristics (classification). • 3695 Explain insulin resistance.• 3699 Compare and contrast type 1 and type 2 diabetes with respect to

epidemiology, etiology, risk factors, clinical presentation, acute and chronic complications and treatment.

• 3700 Interpret results of an oral glucose tolerance test.• 3701 Discuss the role of, the beta cell, obesity, the liver and the peripheral

cell and genetic factors, in the development of type 2 diabetes.• 3702 Describe the pathological changes in the pancreas for type 2 diabetes.• 3703 Describe the incidence of type 2 with respect to age, gender, race, and

geographical occurrence.• 3704 Describe the following conditions: metabolic syndrome, polycystic

ovarian syndrome and Cushing syndrome. • 3705 Explain the key metabolic abnormalities that lead to insulin resistance.

Understanding Diabetes• Classification• Epidemiology• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• Insulin resistance• Other syndromes: Metabolic Syndrome, Polycystic

Ovarian Syndrome, Cushing’s syndrome

Classification of Diabetes

Type Definition

Type 1 Diabetes Diabetes due to pancreatic beta destruction and prone to ketosis

Type 2 diabetes Diabetes that ranges from insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance

Gestational DiabetesMellitus

Glucose intolerance with onset or first recognition in pregnancy

Other types Variety of uncommon diseases, genetic forms, or diabetes associated with drug use.

TYPE 1 Diabetes TYPE 2 DiabetesProportion of diabetes cases

10% 90%

Pathogenesis Beta cell destruction (usually autoimmune)

Insulin resistance, relative insulin deficiency

Endogenous insulin secretion

Low or absent Variable

Need for insulin therapyRequired for survival

Required in <50%, to improve control rather than for survival

Age of onsetOften <30 (but can occur at any age) Often >40 but even in kids

Body habitus Usually lean Often obese

Genetic component Smaller Very large

Symptoms at onset Acute, severe Often mild, slow onset

Ketoacidosis Yes Rare

Long-term complications present at dx?

No Retinopathy ~20%, CVD relatively common

Diabetes in Canada

• 2.4 million Canadians living with diabetes– 1.9 million formally diagnosed in 2007

• 570,000 Canadians have undiagnosed type 2 diabetes

– Nearly 1 million Ontarians living with diabetes

• 6 million Canadians with pre-diabetes or at high risk of type 2 diabetes– Fastest growing population segments at highest risk!

• Aboriginal• Asian, Southeast Asian, Latin American and African• “Boomers”

The Epidemic: Ethnic Groups at High Risk for DM

Aboriginal Latino

South AsianAsian

African Descent

Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011.

Prevalence of diagnosed diabetes among individuals aged ≥ 1 year, by age group and sex, 2008/09

Diabetes in Canada: Prevalence of Diagnosed Diabetes by age and sex

Prevalence increased with age. The sharpest increase occurred after age 40 years. The highest prevalence was in the 75-79 year age group.

Pre

va

len

ce

(%

)

0

10

15

25

30

1-19

5

20

20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 ≥85 CanadaAge group (years)

Females

Males

Total

Overall Prevalence

6.4%

7.2%

6.8%

Diabetes in Canada: Prevalence of Diagnosed Diabetes 1998/99 to 2008/09Age-standardized prevalence and number of cases of diagnosed diabetes among

individuals aged ≥ 1 year, 1998/99 to 2008/09

3.3%

5.6%


Canada: Diabetes Projection

1998 2010 2020

Canadian Diabetes Association, Economic Report 2009, www.diabetes.ca.

1998: 4.8% of population



Prevalence of Diabetes among Individuals aged 20-79 years, Europe, North America, Oceania, 2010

Diabetes in Canada: Prevalence by Province and Territory


NL6.5%

ON 6.0%

QC 5.1%

PE5.6%

NB5.9%

NS 6.1%

MB 5.9%

SK 5.4%

AB 4.9%

BC 5.4%

NT 5.5%

YT 5.4%

NU 4.4%

† Age-standardized to the 1991 Canadian population.

Age-standardized† prevalence of diagnosed DM among individuals ≥ 1 year, 2008/09

NL, NS and ON had the highest prevalence, while NU, AB and QC had the lowest.

< 5.0

5.0 < 5.5

5.5 < 6.0

6.0 < 6.5

≥ 6.5

Diabetes: prevalence in Canadian Aboriginal peoples

Diabetes in Canada, National Statistics and Opportunities for Improved Surveillance, Prevention, and Control. Minister of Public Works and Government Services Canada, 1999.

% w

ith

dia

bet

es

Age group

1 2 35

10

18

23

0

5

10

15

20

25

15-19 20-24 25-29 30-39 40-49 50-64 65+

The Causes of Type 2 Diabetes• Genetics Aspects

– High concordance in identical twins– Family History of Diabetes/Insulin resistance– Ethnicity– Many candidate genes (polygenic is the most

common although there are monogenic forms)• Lifestyle Factors

– Diet– Physical inactivity

FPG ≥7.0 mmol/LFasting = no caloric intake for at least 8 hours

or

A1C ≥6.5% (in adults)Using a standardized, validated assay, in the absence of factors that affect the

accuracy of the A1C and not for suspected type 1 diabetes

or

2hPG in a 75-g OGTT ≥11.1 mmol/Lor

Random PG ≥11.1 mmol/L Random= any time of the day, without regard to the interval since the last meal

Diagnosis of Diabetes

In the absence of symptomatic hyperglycemia, if a single laboratory test is in the diabetes range, a repeat confirmatory laboratory test (FPG, A1C, 2hPG in a 75-g OGTT) must be done on another day. It is preferable that the same test be repeated (in a timely fashion) for confirmation. If results of two different tests are available and both are above the diagnostic cutpoints, the diagnosis of diabetes is confirmed.

Confirmatory Laboratory Test

Diagnostic Testing With 3 Different Tests

Dealing with Discordance

•Many people identified as

having diabetes using A1C will

not be identified as having

diabetes by traditional glucose

criteria, and vice versa.

• When results of more than one test are available (amongst FPG,

A1C, 2hPG in a 75-g OGTT) and the results are discordant, the test

whose result is above diagnostic cut-point should be repeated, and

the diagnosis made on basis of the repeat test.

FPG 2hPG

A1C

Pros and Cons of Diagnostic TestsTest Advantages Disadvantages

FPG Established standardFast and easySingle Sample

Sample not stableDay-to-day variabilityInconvenient to fastGlucose homeostasis in single time point

2hPG in 75 g OGTT

Established standard Sample not stableDay-to-day variabilityInconvenient, UnpalatableCost

A1C ConvenientSingle sampleLow day-to-day variabilityReflects long term [glucose]

$$$Affected by medical conditions, aging, ethnicityStandardized, validated assay requiredNot used for age <18, pregnant women or suspected T1DM

Considerations when using A1C for Diagnosis

• Need validated standardized assay

• Repeat confirmatory test on another day

• Recognize conditions leading to misleading A1C

• A1C is not used for diagnosis in children,

adolescents, pregnancy or suspected type 1 diabetes

• Ethnicity and age can affect A1C results

Recognize pitfalls of A1C: conditions that can affect

valueFactors affecting A1C

Increased A1C Decreased A1C Variable Change in A1C

Erythropoiesis B12/Fe deficiency Decreased erythropoiesis

Use of EPO, Fe, or B12Reticulocytosis Chronic liver Dx

Altered hemoglobin

Fetal hemoglobin Hemoglobinopathies Methemoglobin

Altered glycation Chronic renal failure (use of EPO decreases A1C)

ASA, vitamin C/E Hemoglobinopathies ↑ erythrocyte pH

Erythrocyte destruction

Splenectomy HemoglobinopathiesChronic renal failureSplenomegalyRheumatoid arthritisHAART meds, RibavirinDapsone

Assays HyperbilirubinemiaCarbamylated HbETOHChronic opiates

Hypertriglyceridemia

Diagnosis of Prediabetes*Test Result Prediabetes Category

Fasting Plasma Glucose(mmol/L)

6.1 - 6.9

Impaired fasting glucose (IFG)

2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/L)

7.8 – 11.0 Impaired glucose tolerance (IGT)

GlycatedHemoglobin(A1C) (%)

6.0 - 6.4 Prediabetes

* Prediabetes = IFG, IGT or A1C 6.0 - 6.4% high risk of developing T2DM

A1C Level and Future Risk of Diabetes: Systematic Review

A1C Category (%)5-year incidence of

diabetes

5.0-5.5 <5 to 9%

5.5-6.0 9 to 25%

6.0-6.5 25 to 50%

Zhang X et al. Diabetes Care. 2010;33:1665-1673.

Understanding Diabetes• Classification• Epidemiology• The Metabolic Syndrome• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?

IFG

6060 9090 120120 150150 180180300-30MinutesFasting

Plasma glucose (mmol/l)

8.3

11.1

IGT

DiabetesFPG 7NormalFPG <6

Diabetes

11.1

Normal<7.8

OGTT

Impaired Fasting Glucose, Impaired Glucose Tolerance, and Type 2 Diabetes

Definitions of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance

(IGT) and Diabetes

Fas

ting

Glu

cose

(mm

ol/

L)

3.5

4.5

5.5

6.5

7.5

8.5

3 4 6 8 10 12 14

2-h Post-load Glucose (mmol/L)

Diabetes

IFG + IGT

NormalGlucose

IGT

IFG6.1

6.9

7.8 11.1

* 1. ADA Diabetes Care 2006;29(Suppl 1):S47,2. CDA Can J Diabetes 2003;27(Suppl 2):S7, 3.WHO 1999 NDC/NCS.99.2 accessed Mar 2 2006 from www.who.int

5.6*

Understanding Diabetes• Classification• Epidemiology• The Metabolic Syndrome• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?

Natural History of Type 2 Diabetes

Henry. Am J Med 1998;105(1A):20S-6S.

Normal Impaired glucosetolerance

Type 2 diabetes

Time

Insulinresistance

Insulinproduction

Glucoselevel

b-celldysfunction

Normal Insulin Secretion

Insulin secretio

n

early peak

late phase

minutesGlucose stimulus

Release of pre-formed insulin

Synthesis and release of newly formed insulin

5 10 15 20 25 30

Hosker J. Metabolism 1989;38(8):767-772

Diminishedinsulin

Hyperglycemia

Liver

1. Insulin deficiency

2. Excess glucose output

3. Insulin resistance

Pancreas

Muscle and fat

Excess glucagon

Islet

Diminishedinsulin

α-cell produces excess glucagon

β-cell produces less insulin

The pathophysiology of T2DM includes three main defects

Understanding Diabetes• Classification• Epidemiology• The Metabolic Syndrome• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• The Case for Glycemic Control

Prevention of Type 1 Diabetes

• T1DM is a chronic autoimmune condition with destruction of pancreatic beta cells

• Ongoing or completed trials– ENDIT: High-dose nicotinamide – Not effective – DPT-1: Low-dose insulin in high risk relatives – Not effective overall– TRIGR: Exclusion of cow’s milk protein to infants until 6-8 months of

age – Trial ongoing

• Alternate strategy to use immunosuppression / modulation at the time of diagnosis but significant side effects and ethical considerations

Prevention of Type 2 Diabetes

Diabetes Prevention Program (DPP) Research Group. N Engl J Med 2002;346:393-403.

Years

• Benefit of diet and exercise or Metformin on diabetes prevention in at-risk patients

• N = 3234 with IFG and IGT, without diabetes

00

10

20

30

40

1.0 2.0 3.0 4.0

Placebo

Metformin

Lifestyle

Cumulativeincidence of diabetes(%)

31%

58%

P*< 0.001

< 0.001

*vs placeboIFG = impaired fasting glucose, IGT = impaired glucose tolerance

STOP-NIDDM Study

Chiasson JL, et al. Lancet 2002;359:2072-77.

N = 1429 people with IGT, BMI 25-40, 40-70 yrs, 3.3 years follow up

Days after randomization

Cum

ulat

ive

prob

abili

ty

P = 0.0022

0

AcarbosePlacebo

100200

300400

500600

700800

9001000

11001200

1300

1.00

0.95

0.90

0.50

0.45

0.40

0.65

0.60

0.55

0.80

0.75

0.70

0.85

Acarbose25%

Summary of Diabetes Prevention

1. At this time, there are no safe and effective strategies to prevent T1DM

2. Intensive lifestyle modification with weight loss can reduce the risk of progression from pre-diabetes to T2DM by almost 60%

3. Progression from pre-diabetes to T2DM can be reduced by Metformin or Acarbose by approximately 30%

Definition of Insulin Resistance

• A state in which a given concentration of insulin produces a less-than-expected biological effect

• Disorders associated with insulin resistance:• Obesity• Prediabetes/diabetes• Metabolic syndrome• Polycystic ovarian sundrome• Endocrine disorders – Cushing’s syndrome, acromegaly• Genetic conditions• Use of medications – steroids, cyclosporine, niacin, protease inhibitors

• Insulin resistance also occurs with aging

Pathophysiology of insulin resistance

• Insulin receptor mediated: • Decreased number (as occurs in obesity)• Postreceptor failure in signalling pathway (mutations in

receptor, signalling proteins, GLUT4)• Autoantibodies to insulin receptor

• Defects in signalling mediators:• Glucose• Free fatty acids• Autonomic nerves• Gut hormones (GLP-1)• Adipokines – high leptin and adiponectin, low ghrelin

Metabolic Syndrome

A constellation of risk factors • Significantly increased CVD risks• Significantly increased risks for type 2

diabetes

Clinical Features of the Metabolic Syndrome

• Abdominal obesity• Hyperglycemia• Atherogenic dyslipidemia• Hypertension• Proinflammatory state• Prothrombotic state

Definition of Metabolic Syndrome

Metabolic Syndrome –Treatment

• A common condition associated with increased cardiovascular disease risks

• Treatment is aimed at lifestyle modification to achieve desirable body weight and reduce abdominal obesity

• Multiple medical therapy may be required to achieve metabolic targets (lipids, glucose and BP)

Fat mass : 19.8 kg

VAT : 155 cm2

Fat mass : 19.8 kg

VAT : 96 cm2

Visceral fat is a better marker than weight or general obesity

300

250

200

150

100

50

060 80 100 120

Waist circumference (cm) V

isce

ral A

T (

cm2 )

r = 0.80Front

Back

Waist

HipSubcutaneous AT

Visceral AT

Waist circumference: a simple measurement thatcorrelates well with visceral obesity

AT= Adipose tissue

The Metabolic Syndrome

Polycystic Ovarian Syndrome

• Major features:• Menstrual dysfunction (oligomennorhea)• Anovulation• Hyperandrogenism (hirsutism, acne) • Metabolic abnormalities – higher risk of diabetes type 2, dyslipidemia and

hypertension• Obesity

• Abnormal hypothalamic-pituitary-ovarian axis• Although ovarian cysts are commonly present it is not a requirement for

diagnosis (many women have ovarian cysts without the other features of PCOS)

• Insulin resistance: related to postbinding defects in insulin receptor and may have gonodatropin-augmenting effects on ovarian function

• Diagnostic criteria (Rotterdam Criteria), must have 2 out 3:

• Irregular or absent ovulation• Elevated androgen hormones (clinical or biochemical)• Enlarged ovaries containing at least 12 follicles each

Must exclude other causes of androgen excess

Cushing’s Syndrome

• Condition characterized by prolonged exposure to elevated levels of endogenous or exogenous glucocorticoids

• Endogenous production may be due to:• ACTH dependent mechanisms (hypothalamic/pituitary

overproduction, paraneoplastic syndrome such as smallc ell lung ca)

• ACTH independent (adrenal tumor)

Clinical features suggestive of Cushing’s syndrome

• Onset well after menarche• Fat redistribution/weight gain

– Especially supraclavicular area

• Catabolic effects present– Thinning of skin– Easy bruising– Abdominal striae– Poor wound healing– Osteoporosis

• Associated mood/cognitive changes

Steps in diagnosing

• Does patient have too much glucocorticoid– Screening test– (confirmatory test)

• Etiology– ACTH dependent or independent– Source - imaging

Screening Tests

24 hr UFC800 and 2200 (not 1600) cortisol (salivary or serum)

1 mg. ON dex suppression

understanding diabetes and insulin resistance syndromes dr. amel arnaout

Documents

insulin resistance syndromes

autoimmune insulin resistance

insulin therapy

ketosis type

development of type

contrast type

incidence of type

metabolic syndrome