Obesity, Insulin Resistance, and Metabolic Syndrome

insulin is released by what in response to ?

Released by β-cells of the pancreas in response to ↑ plasma glucose levels

insulin binds to _______ on target tissues on adipose tissue, liver, skeletal, muscle

insulin receptors

what is insulins effect on adipose tissue?

Enhances glucose uptake by adipocytes

↑ Lipogenesis & ↓ Lipolysis

what is the most sensitive pathway of insulin action?

Inhibition of lipolysis in adipose tissue

what are the effects of insulin on skeletal muscle?

Enhances glucose uptake by skeletal myocytes

↑ Glycogenesis & ↓ Glycogenolysis

↑ Protein synthesis & ↓ protein breakdown

glucose uptake by hepatocytes is insulin-mediated t/f

false

what are the effects of insulin on the liver?

↑ Glycogenesis

↓ Glycogenolysis

↑ Lipogenesis

"Low insulin sensitivity" =

insulin resistant

insulin resistance (IR)

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

what does IR result in?

hyperinsulinemia

as levels of insulin increases, what happens to the receptors?

decrease

how does IR affect adipose tissue?

Impaired insulin-stimulated glucose uptake by adipocytes

↓ Lipogenesis & ↑ Lipolysis

The "downward spiral" of lipolysis seen in IR and adipose tissue =

lipotoxicty

how does IR affect skeletal muscle?

Impaired insulin-stimulated glucose uptake by skeletal myocytes

↓ Glycogenesis & ↑ Glycogenolysis

↓ Protein synthesis from AA

↑ protein breakdown into AA

As in adipose tissue, any insulin receptor stimulation that DOES occur in skeletal muscle is muted/attenuated which ?

perpetuates the cycle of IR

IR & its resulting hyperinsulinemia still stimulates the liver to ?

↑ Glycogenesis & ↓ Glycogenolysis

↑ Lipoprotein (VLDL) formation

When glucose is unavailable to tissues for fuel, the liver makes alternative sources of energy. what 2 process are increased?

↑ Gluconeogenesis

↑ Ketogenesis

what are the 3 physiologic ketones produced by the human body?

Acetone

Acetoacetic acid/acetoacetate (AcAc)

β-hydroxybutyric acid/β-hydroxybuterate (β-HBA)

what is the largest risk factor for IR?

metabolic obesity

obesity is the state of excess adipose tissue mass and an increase in what 3 things?

number of adipocytes (hyperplasia)

lipid deposition within adipocytes (adipocyte hypertrophy)

tissue macrophages within adipose tissue

what does true "obesity" imply?

↑ morbidity & mortality

what is the difference between visceral and subcutaneous adipose tissue?

visceral or central is located deep in the abdominal cavity and is more metabolically active

subcutanous or peripheral is located just beneath the skin commonly located in the lower extremities/buttocks

what is the most widely used method to gauge obesity?

BMI

what are the NIH definitions for adult BMI?

Normal

18.5-24.9 kg/m2

Overweight

25-29.9 kg/m2

Obesity

≥ 30 kg/m2

Grade/Class I: 30-34.9 kg/m2

Grade/Class II: 35.39.9 kg/m2

Grade/Class III (Extreme/Morbid/Severe Obesity): ≥ 40 kg/m2

what other anthropomorphic measurements (other than BMI) are useful in accessing metabolic syndromes?

waist circumference

waist to hip ratio

waist to height ratio

why is visceral fat more more susceptible to ↑↑↑ lipolysis?

Insulin receptors in visceral adipose tissue have a lower affinity for insulin which impairs the ability of insulin to suppress lipolysis

Visceral adipose tissue is more sensitive to the stimulatory effects of the counter-regulatory hormones that ↑ blood glucose (usually via glucagon)

what are 2 counter-regulatory hormones that ↑ blood glucose?

epinephrine and cortisol

how can adipokines act as cytokines?

creating a pro-inflammaotry state by drawing macrophages & other inflammatory mediator to various tissue surfaces

Central (visceral) adipose tissue drains directly into the portal vein which exposes liver to ↑ levels of FFA & altered adipokine levels and stimulates the liver to produce what 2 things?

C-reactive protein (CRP)

Fibrinogen

hunger and "overfeeding" is seen in IR due to the shortage of fuel for cellular function and dysfunction of what appetite/satiety hormone?

leptin

what is "pancreatic poop out"?

when the compensatory mechanism of the pancreas producing sufficient insulin to regulate blood glucose fails

explain the process when an insulin resistant person eats food

Food ↑BG → Pancreas secretes Insulin in response to ↑BG → IR prevents insulin & glucose from entering cell → Cells don't have fuel* so you feel hungry & eat more

explain the progression of insulin resistance

postprandial hyperinsulinemia --> fasting hyperinsulinemia --> hyperglycemua and glucose intolerance --> type 2 DM

what are 2 features that can be seen in patients with IR and dyslipidemia? which is an excellent marker of IR?

Hypertriglyceridemia (↑TG)**

Low high-density lipoprotein (↓HDL)

when fasting TG is ~180 mg/dL what is there a predominance of?

sdLDLs

how can hyperinsulinemia and IR lead to hypertension and hyperuricemia?

HTN

Vasoconstriction

Inhibition of NO synthesis & its vasodilatory effects

↑ Activity of the SNS

Salt and water retention

↑ Renal reabsorption (↓ excretion) of Na+

HYPERURICEMIA

↑ Synthesis of uric acid

↑ Renal reabsorption (↓ excretion) of uric acid

how can metabolically active adipose tissue lead to hypertension?

Activation of the RAAS pathway

↓

Salt & water retention angiotensinogen-like substance & vasoconstriction

↓

HTN

in IR there is a predominace of sdLDLS, dysregulated adipokines act as cytokines, and there is metabolically active adipose tissue that all leads to what 2 things?

inflammation and hypercoagulability

what is metabolic syndrome?

Cluster of metabolic abnormalities that increase risk of T2DM and CVD

what is the goal for a patient with metabolic syndrome?

decrease overall cardiac M&M

what is the driving force behind the development of metabolic syndrome?

obesity

what is the pathophysiology of metabolic syndrome?

insulin resistance (HYPERinsulinemia)

name some clinical features of metabolic syndrome

↑ Waist circumference/central adiposity

Adipokine dysregulation

Pro-inflammatory cytokine excess

Insulin resistance (IR)

Impaired glucose tolerance (IGT)

Atherogenic dyslipidemia (↑TG & sdLDLs, ↓HDL)

Hypertension (HTN)

Hyperuricemia

↑ Prothombotic factors (fibrinogen, PAI-1)

Endothelial dysfunction

what is the NCEP/ATP III criteria for metabolic syndrome?

Three or more (≥3) of the following criteria: central obesity, hypertriglyceridemia, low HDL, elevated blood pressure, hyperglycemia

name 3 associated conditions that can be seen with metabolic syndrome?

liver disease, PCOS, obstructive sleep apnea

what is sometimes seen on physical exam in patients with severe insulin resistance? (hyperpigmentation in folded areas)

Acanthosis nigricans

what is the most important component for weight reduction in obesity management?

caloric restriction

what is the most important component for maintenance of weight loss?

physical activity

what are 2 options other than lifestyle intervention for patients with significant obesity? what is the BMI for each?

Weight loss medications

BMI ≥30 kg/m2

Bariatric surgery

BMI ≥40 kg/m2

popular weight loss medications such as ozempic and wegovy are what kind of medications?

GLP-1 receptor agonists (GLP-1 RAs)

what is the first choice for dyslipidemia therapy for a patient with metabolic syndrome?

statins

what is the first choice for hypertensive therapy for a patient with metabolic syndrome?

ACE/ARBs

what are 2 common "insulin-sensitizers" used for hyperglycemia therapy?

Biguanides [metformin (Glucophage®)]

Thiazolidinediones (TZDs)

how frequent should a patient with metabolic syndrome follow up with there provider?

individualized to patient