Physiology of Type 2 Diabetes

Question 1

What is type 2 diabetes?

Answer 1

Patients with type 2 diabetes gradually develop beta cell dysfunction causing a relative insulin deficiency

• their insulin secretory capacity is not sufficient to overcome defects in insulin action (insulin resistance)

Prior to the onset, the body’s cells become resistant to the effects of insulin, requiring the pancreas to produce more insulin in an effort to control blood glucose

• Insulin resistance is usually attributed to the presence of obesity and insulin secretion is high before the onset of hyperglycemia

Question 2

Why don’t type 2 diabetics develop diabetic ketoacidosis?

Answer 2

Their insulin secretion does not drop to zero

Question 3

What is the pathogenesis of Type 2 Diabetes?

Answer 3

A heterogenous disorder characterized by:

deficient insulin secretion (relative insulin deficiency)

insulin resistance

Question 4

How is insulin resistance related to obesity?

Answer 4

In obesity, insulin resistance develops in the major insulin target tissues: adipose tissue, muscle, and liver

Contributing factors: abnormalities of lipid metabolism and/or secretion of adipose tissue dervied proinflammatory mediators

Degree of insulin resistance can vary from one tissue to another

Some patients with insulin resistance develop a physical finding called acanthosis nigricans - consists of skin that is darkened, velvety, and thick found at the back of the neck (may be confused with dirt), axillae, or groin

Question 5

Describe adipose tissue physiology

Answer 5

More than just a storage depot for excess energy

Composed of several cell types: Adipocytes, Preadipocytes, Endothelial cells, and immune cells (macrophages and lymphocytes)

Question 6

What are the adipose tissue products (adipokines)?

Answer 6

Adipocytes secrete a variety of physiologically active substances: adipokines and hormones, which may improve insulin sensitivity

• hormones include: leptin and adiponectin (increased adiponectin improves insulin sensitivity, particularly in the liver)
• leptin acts on the hypothalamus to influence appetite and energy expenditure

Inflammatory cytokines: TNFalpha, IL-6, IL-1beta, others

Enzymes: Aromatase

Growth factors

Prostacyclins

Question 7

Describe the neuroendocrine regulation of energy balance and how it relates to leptin, alpha-MSH, Agout-related peptide, and Ghrelin.

Answer 7

Leptin (from adipose tissue) ats on the hypothalamus to stimulate the synthesis of the neuropeptide alpha-MSH, which is derived from a precursor peptide proopiomelanocortin (POMC)

Alpha-MSH acts on hypothalamic melanocortin receptors (MCAR) to inhibit appetite

Agouti-related peptide (AgRp) prevents alpha-MSH from exerting its inhibitory effects on MCAR, thereby stimulating appetite

Ghrelin, derived from cells of the stomach, stimulates feeding

Endocannabinoid system is also involved in stimulating appetite

Question 8

What happens to adipose tissue in persons with obesity?

Answer 8

Adipocytes become larger (hypertrophic) and secrete less adiponectin which leads to decreased insulin sensitivity

Contains increased numbers of macrophages, which secrete chemokines that recruit aditional macrophages

macrophages also secrete inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha)m, IL-6, and IL-1beta, which may alter insulin signaling pathways within adipocytes

Altered metabolism and gene expression in adipocytes causes increased adipocyte lipolysis and greater release of free fatty acids (FFA)

Question 9

What is ectopic fat accumulationg and how does it relate to obesity?

Answer 9

Increased lipolysis and release of FFA from inflamed, insulin resistant adipose tissue makes more FFA available to the liver and other tissues

Greater uptake of FFA causes changes to liver metabolism that contribute to insulin resistane

When energy intake exceeds energy expenditure in a person whose adipocytes are already enlarged, lipid can be deposited in ectopic sites such as liver and muscle

Lipid can accumulate within hepatocytes of obese persons causing liver steatosis and liver Kupffer cells may increase production of inflammatory mediators

Adipocytes can also accumulate in the muscle, where they surround myocytes and play a role in development of muscle insulin resistance

Question 10

Diagram how obesity can lead to inflammation and insulin resistance

Answer 10

Obesity -> inflammation + insulin resistance

In Adipocytes:

• Adipocyte hypertrophy
• macrophage recruitment
• Increase proinflammatory cytokine production
• Increase lipolysis

-> ectopic lipid in liver

• increase glucose production
• liver steatosis
• kupffer cell activation
• increase cytokine production

-> ectopic lipid in muscle

• decrease glucose uptake
• increase FFA uptake
• Increase extramyocellular adipose
• macrophage recruitment

Question 11

Describe how diabetes is a pro-inflammatory and pro-coagulant state

Answer 11

In addition to its secretion of other inflammatory cytokines, adipose tissue from obese persons increases production of plasminogen activator inhibitor-1 (PAI-1)

PAI-1 is a prothrombic substance that promotes hypercoabulability and increases cardiovascular risks

Question 12

Describe the difference abdominal obesity has to normal obesity.

Answer 12

Secretory products and lipid metabolism of adipocytes in various body locations differ

Adipose tissue in areas surrounding the abdominal organs (visceral adipose tissue) appears to differ from adipose tissue in subcutaneous locations with respect to insulin resistance: obese persons who adipose tissue is located primarily in areas surrounding their abdominal organs are more likely to develop insulin resistane and are greater risk for developing cardiovascular complications of diabetes

Question 13

How would you assess obesity in clinical practice?

Answer 13

waist circumference: an indiret measure of central adiposity correlated with visceral fat

waist circumference is measured at the high point of the iliac crest at minimal respiration to the nearest 0.1cm

Waist circumference: men >40in; women >35in

Question 14

What is the body mass index?

Answer 14

An estimate of body fat calculated based on height and weight

BMI = weight (kg)/height(m) squared

BMI = weight (pounds) x 703/height(inches) squared

BMI is clinically useful because it correlates with health risks (hypertension, diabetes, cardiovascular disease)

Question 15

What are some limitations of the BMI?

Answer 15

BMI categories may not apply to all populations - some populations develop obesity-associated health risks at lower BMI

In muscular adults such as athletes, high lean body mass (muscle) may contribute to a high BMI

• consider this possibility in persons with BMI between 25 and 35 and a waist circumference of <40in (men) or <35in (women)
• individuals with increased BMI AND normal waist circumference have lower health risks than individuals with an increase of both BMI and waist circumference

In older persons who have lost muscle, the BMI may underestimate body fat

Asian-Americans: the relationship between BMI and risk for diabetes is shifted to lower BMI values

Question 16

What is metabolic syndrome and how does it relate to type 2 diabetes?

Answer 16

Metabolic syndrome = group of disorders clustered together in each patient

Hypertension, Abnormal lipids (Dyslipidemia), Type 2 diabetes, and Obesity

Patients with metabolic syndrome are more likely to develop type 2 diabetes and cardiovascular disease

patients with components of metabolic syndrome have increased cardiovascular risks; if these patients don’t already have type 2 diabetes, they are very likely to develop it

Question 17

How is dyslipidemia associated with obesity, insulin resistance, and type 2 diabetes?

Answer 17

Dyslipidemia in type 2 diabetes and in ‘metabolic syndrome’ is characterized by decreased plasma high density lipoproteins (HDL) and increased triglycerides

Hypertriglyceridemia occurs as a result of increased hepatic synthesis and secretion of VLDLs, although plasma LDL conc may be normal, the structure is abnormal

patients with diabetes have smaller more dense LDL particles that are ‘atherogenic’ and would benefit from treatment with a ‘statin’ (HMG-CoA reductase inhibitor)

Question 18

What is the criteria for diagnosing metabolic syndrome?

Answer 18

Presence of 3 or more of the following criteria *

Abdominal obesity (waist circumference) men >40in; women >35in

Hypertriglyceridemia >= 150mg/dL

Low HDL cholesterol: men <40mg/dL; women <50 mg/dL

High blood pressure >130/85 mmHg

High fasting blood glucose > 100mg/dL

Question 19

What is the pathophysiology of type 2 diabetes?

Answer 19

increase hepatic glucose production -> increase [glucose]

decrease glucose uptake in muscles and adipose tissues

-> impaired insulin secretion

insulin resistance

Question 20

What is hyperglycemia in type 2 diabetes a result of?

Answer 20

Increased hepatic glucose production

Decreased glucose uptake by muscle and adipose tissue

Impaired insulin secretion

Question 21

What is the pathogenesis of type 2 diabetes?

Answer 21

the ‘ominous octet’

decreased insulin secretion -> hyperglycemia

decreased incretin effect -> hyperglycemia

increased lipolysis in adipose tissue -> hyperglycemia

increased glucose reabsorption in kidneys -> hyperglycemia

decreased glucose uptake in muscles -> hyperglycemia

neurotransmitter dysfunction -> hyperglycemia

increased HGP in liver -> hyperglycemia

increased glucagon secretion in islet-alpha cell -> hyperglycemia

Question 22

Describe the pathophysiology of hormone resistance as it relates to insulin resistance

Answer 22

Insulin resistance = diminished response to endogenous or exogenous insulin

it can be caused by:

1. post-receptor defects in cell metabolism -> decrease biologic response
   - beta cells try to overcome insulin resistance by secreting more insulin -> down-regulation of insulin receptors (decrease in receptor number in response to sustained high conc of hormone), which only worsens the insulin resistance -> beta cells secrete more insulin
2. diminished number of receptors
3. defective receptors (rare)

Question 23

How are hormones released in healthy persons?

Answer 23

In healthy persons, pulsatile secretion of insulin prevents down-regulation of insulin receptors

resulting peaks and troughs prevent down-regulation of receptors, thereby maintaining tissue sensitivity to insulin

increased amplitude and/or frequency of individual pulses can create a peak, but peak conc return to low baseline in healthy persons

Question 24

What is the insuline dose-response curve?

Answer 24

The cellular response to increasing insulin conc is a continuous increase in receptor occupancy and biologic action until the critical number of occupied receptors needed to generate a maximal response is reached

Further increases in the prevailing insulin conc beyond this point lead to greater receptor occupancy with no further increase in biologic response

Question 25

How do changes in insulin receptor number affect the dose-response curve?

Answer 25

In a healthy individual, all the insulin receptors on a target tissue do not need to be occupied to produce a maximal biologic effect

• max insulin stimulation of glucose transport in isolated adipocytes (fat cells) occurs when only 10% of their insulin receptors are occupied
• remaining 90% have been called ‘spare’ - without them, the likelihood of insulin binding to one of its receptors decreases and insulin sensitivity decreases

Decreased numbers of insulin receptors are commonly found in patietns with diabetes and/or type 2 diabetes

• down-regulation of insulin receptors occurs in the presence of high concentrations of insulin

Question 26

How do the changes in post-receptor signaling affect the dose-response curve?

Answer 26

If there is an abnormality in a specific rate-limiting step in the hormone action pathway following hormone-receptor binding, it is possible that a maximal biologic response may not be generated even at very high hormone concentrations

in patients with obesity and/or type 2 diabetes, insulin resistance usually develops from a combo of post-receptor defects in insulin action plus decreased insulin receptor number

• insulin dose-response curve in such patients would like show a shift to the right (from down-regulation of insulin receptors) plus a lower than maximal response even at high insulin concentrations (from post-receptor abnormalities in insulin action)

Question 27

How does the development of type 2 DM occur?

Answer 27

Occurs gradually over a period of years

Symptoms of polyuria and nocturia develop gradually, so pt may attribute to other causes

Pt may have impaired glucose tolerance or early stages of type 2 diabetes for several years, which explains why patients may already have neuropathy at the time of diagnosis

increased CV risks begin much earlier, prior to beta cell dysfunction and impaired insulin secretion

Many have metabolic syndrome and may spend years in a state of insulin resistance, chronic inflammation, hypercoagulability, and dyslipidemia prior to diagnosis

Question 28

What is a potential progression of the onset of type 2 diabetes?

Answer 28

Metabolic Syndrome (hyperinsulinemia/cardiovascular disease risks) -> peripheral insulin resistance -> impaired glucose tolerance -> early diabetes -> beta cell failure, apoptosis/late diabetes

Question 29

How does the rate of insulin secretion relate to beta cell dysfunction in diabetes?

Answer 29

As people become obese and insulin resistance develops, insulin secretion is high as the beta cells try to compensate for insulin resistance and maintain normoglycemia - this is the time when components of the metabolic syndrome become established and cardiovascular risk begins to escalate

Once beta cells are not able to keep up with the need for excess insulin, patients develop hyperglycemia (either fasting or following meals)

Initially, the patient has ‘pre-diabetes’ with increased risk for going on to develop type 2 diabetes

Question 30

What are the categories of increased risk for diabetes (prediabetes)?

Answer 30

Impaired fasting glucose (IFG)

Impaired glucose tolerance (IGT)

HbA1c 5.7-6.4%

Question 31

What is the timeline of development of type 2 diabetes?

Answer 31

Over time, beta cell insulin secretion continues to decrease as beta cells suffer from glutotoxicity, oxidative stress, lipotoxicity, islet inflammation, islet amyloid deposition, and many forms of dysregulation

Glucose risesa nd eventually critera for diabetes are met

over the course of many years, the beta cells may sustian so much inflammation and injury that patients with type 2 DM may eventually reiuqre insulin to manage diabetes

Question 32

What is an oral glucose tolerance test (OGTT)?

Answer 32

After an overnight fast, the glucose is measured and then the patient is given a solution containing 75g of glucose to drink

Insulin secretion is biphasic:

the first phase of glucose-induced insulin secretion occurs very rapidly (within a few mins) and represents the release of insulin from a pool of easily accessible insulin secretory granules

second phase occurs later (peak at 1-2hrs) and represents the release of insulin from a more slowly accessible pool of insulin secretory granules

in patients with type 2 DM, the first phase of insulin secretion becomes subnormal or is lacking entirely

• loss of this early phase of insulin secretion can contribute to postprandial (post meal) hyperglycemia

Question 33

Describe the relationship between insulin resistance and obesity.

Answer 33

Obese persons secrete more insulin and have higher insulin levels than lean persons because their beta cells are secreting more insulin in an effort to overcome insulin resistance

in obese persons, insulin resistanec is usually reversible by dietary restriction and weight reduction

• this improvement occurs even with a minor degree of weight loss
• losing approximately 7% of body weight can preent or delay the development of type 2 diabetes (if the weight loss is sustained)

Question 34

What does it mean that patients with type 2 DM have a relative rather than absolute deficiency of insulin?

Answer 34

Their insulin levels may be higher than normal, but may not be sufficiently high to overcome their degree of insulin resistance

A combination of insulin resistance and impaired insulin secretion together result in type 2 diabetes

insulin resistance is present prior to the development of impaired glucose tolerance (prediabetes) or type 2 diabetes

• hyperglycemia develops as a result of beta cell dysfunction that limits insulin secretion
• once a patient has developed impaired glucose tolerance or type 2 diabetes, insulin resistance is partially reversible with weight reduction

Question 35

Compare the characteristics of the two major types of diabetes.

Question 36

What is the genetic predisposition for development of diabetes?

Answer 36

A disease is considered ‘genetic’ if concordance is 100%

for type 1 DM, concordance is 30-65%

for type 2 DM, concordance is 90-100%

Strong genetic component for type 2 diabetes, which may be related to the fact that obesity is a predisposing factor

Question 37

what are the lifestyle recommendations for all patients with diabetes or increased risk for diabetes?

Answer 37

healthy eating

weight control

increased physical activity

smoking cessation

Question 38

What is the diabetes prevention program (DPP)?

Answer 38

Intensive lifestyle therapy reduced cardiovascular risk better than metformin therapy or placebo

• achieve and maintain weight reduction of at least 7% of initial body weight -> lower systolic and diastolic BP, triglycerides, atherogenic LDL, increased HDL, and less diabetes!

Question 39

How should you manage obesity in clinical practice?

Answer 39

Stages of Change:

Preconteplation: not ready for change

Contemplation: thinking about change

Preparation: getting ready to make a change, planning, and commitment

Action: making the change, implementing the plan, and taking action

Maintenance: sustaining and integrating behavior change

Relapse/Recycling: slipping back to previous behavior and reentering cycle

Question 40

How should you set realistic goals and over come obstacles?

Answer 40

Patient must be in control

“find a program for yourself that you can follow for the rest of your life”

weight loss is a gradual process * easy to be discouraged if focus is on weight

focus on better food choices rather than weight loss

meal planning enables the patient to eat satisfying portions of healthy foods

Question 41

What are the barriers to healthy eating?

Answer 41

Convenience

Energy density/cost

Taste/variety

To promote good health

Concerns about food-borne illness

Restricted by allergy or intolerance

Ethinc/family traditions

Availability

Question 42

How does exercise enhance insulin actions?

Answer 42

During exercise, a decrease in insulin secretion lowers the insulin to glucagon ratio (allowing the liver to produce and export glucose) while GLUT4 are translocated to the muscle plasma membrane by exercise itself rather than by insulin (allowing enough glucose to enter exercising muscles)

one can consider exercise a state of increased insulin sensitivity (more GLUT4 translocation at a lower insulin concentration)

Exercise helps expend energy and promote weight loss in obese persons and it improves cardiovascular fitness