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Pathophys Semester II > Exam III Pancreas-PT1 DM > Flashcards

Exam III Pancreas-PT1 DM Flashcards

1
Q

Pancreas Physiology in a Nutshell- Exocrine Pancreas

A

Composed of acinar cells that secrete proenzymes needed for digestion:

  • Trypsinogen
  • Chymotrypsinogen
  • Procarboxypeptidase
  • Proelastase
  • Kallikrenogen
  • Prophospholipase

Proenzymes and enzymes are carried by Ducts to the duodenum where they are activated.

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2
Q

Pancreas Physiology in a Nutshell - Endocrine Pancreas

A

Composed of the islets of Langerhans that secrete:

  • Insulin by B cells
  • Glucagon by a cells
  • Somatostatin by δ cells
  • PP cells secrete pancreatic polypeptide
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3
Q

Overview of DM

A

DM is a group of metabolic disorders sharing common feature of hyperglycemia.

Hyperglycemia is diabetes caused by

  • Defects in insulin secretion
  • Insulin action
  • Or most commonly, both

The Chronic hyperglycemia and associated metabolic dysregulation might cause:

-secondary damage in multiple organ systems, especially the kidneys, eyes. Nerves and blood vessels

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4
Q

Regulation of Glucose Homeostasis

A

After a meal -> Insulin in normal subjects:

  • It decreases liver glucose production by decreasing both glycogenolysis and gluconeogenesis.
  • It increases glucose intake by skeletal muscle and adipose tissue by translocating glucose transporters
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5
Q

Response to Hypoglycemia in Normal subjects

A

Counter regulatory hormones

Relation between insulin and glucagon

-In the earliest stages (within minutes)

–Decreased insulin

–increased glucagon

Behavioral defenses

-The initial symptoms of sweating, anxiety, palpations, hunger and tremor -> plasma glucose concentration falls below 55 mg/dL (3.1 mmol/L)

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6
Q

Responses to Hypoglycemia in Diabetes

A

Impairment of behavioral and counter-regulatory responses

HAAF

Nocturnal hypoglycemia

  • Direct relationship between overnight blood glucose and the following morning level
  • Causes of morning hyperglycemia are nocturnal growth hormone secretion and hyperinsulinemia

Exercise

-Increases glucose utilization by muscle can cause hypoglycemia in PTs with insulin-deficient diabetes

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7
Q

Hypoglycemia-Associated Autonomic Failure (HAAF) in Diabetes

A

HAAF definition:

  • The clinical syndromes of defective glucose counter-regulation and hypoglycemia unawareness
  • Hypoglycemia, even if asymptomatic, causes a vicious cycle of recurrent hypoglycemia

HAAF mechanism

-reducing the sympathoadrenal response to subsequent hypoglycemia due to:

–changes hypothalamic functions

–increase in cortisol

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8
Q

Glucose Transporters

A

The most important stimulus for insulin synthesis and release in Glucose itself

Glucose enters beta cells via the glucose transporter, GLUT2, which causes the release of insulin into the bloodstream to bind to insulin receptors

Glucose Utilization:

-Insulin stimulates glucose uptake by skeletal muscle and fat by GLUT4

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9
Q

Glucose transporters

A

Intestine, kidney: energy-dependent sodium/glucose co-transporters

Other cells: diffusion via GLUTs 1-5

GLUT2: Beta cells, liver; low-affinity; post-prandial action

GLUT3: All tissues; major transporter in neurons or CNS

GLUT4: skeletal muscle, fat cells, insulin stimulates translocation from cytosol to cell membranes

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10
Q

Metabolic actions of insulin

A

Effect of insulin on metabolism of:

  • Glucose
  • Fat: decrease lipolysis
  • Protein: inhibits breakdown
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11
Q

Clinical Pearl: Measuring Glycemic Control

A

Clinical test to estimate blood glucose control:

-Measurement of glycated hemoglobin (also called A1C, hemoglobin A1C, glycohemoglobin, or HbA1C)

A1C assy:

A1C reflects mean blood glucose over the entire 120-day lifespan of the red blood cell, but it correlates best with the mean glucose over the previous 8-12 weeks

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12
Q

Diabetes Mellitus Broad Classification

A

Type 1 diabetes:

-An autoimmune disease characterized by pancreatic B cell destruction and an absolute deficiency of insulin

Type 2 diabetes:

-Caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic B cells (“relative insulin deficiency”)

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13
Q

DM 1

A

Definition: An autoimmune disease -> islet destruction by endogenous B-cell antigens

Genetic susceptibility

-HLA region

Autoimmunity:

-Islet cell autoantibodies (ICAs)

Environmental factors

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14
Q

Immunological Response in DM I

A

Immunologic response

  • The antigen binds to MHC class II -> autoimmune injury to the pancreatic beta cells
  • Costimulatory pathways that further increase T cell activation

Risk of DM I

  • The measurement of islet autoantibodies
  • The presence of two or more of these islet autoantibodies
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15
Q

Confirmed targets of autoantibodies in DM I:

A

Insulin

Glutamic acid decarboxylase

Insulinoma-associated antigens 2 (A & B)

AnT8 (zinc transporter)

2 or 3 = DM I

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16
Q

Time Course of DM I

A

Genetic Markers:

-Present from birth

Immune Markers:

First appear at the time of the environmental triggering events

Clinically evident type 1 diabetes does not occur until there has been a much greater loss of functioning beta cells

17
Q

Spectrum of Diabetes Metabolic Abnormalities

A

Diabetic Ketoacidosis (DKA – Mostly DM I) & Hyperosmolar hyperglycemic state (HHS Mostly DM II) in PTs with uncontrolled diabetes:

  • HHS: glucose exceeds 1000 mg/dL (56 mmol/L)
  • Pathogenesis:

–Insulin deficiency and or resistance

–Glucagon excess

  • Ketoacidosis formed by lipolysis -> synthesis of ketones from FFA in the liver
  • Hyperglycemic crises are pro-inflammatory states -> Oxidative stress
18
Q

Pathogenesis of Diabetic Ketoacidosis

A
19
Q

DM II

A

Definition: Complex disease that involves an interplay of genetic and environmental factors and a pro-inflammatory state

NO evidence of an autoimmune basis

Characterized by hypoglycemia, insulin resistance, and relative loss in insulin secretion

Hyperglycemia itself can damage pancreatic beta-cell function and magnify insulin resistance, causing a vicious cycle of hyperglycemia

Definition of metabolic syndrome: Co-occurrence of metabolic risk factors for both DM II and CVD

20
Q

Metabolic defects in DM II

A

Insulin resistance

Inadequate insulin secretion:

-Due to the genetic alteration affecting GLU-2 expression

Impaired insulin processing

-The processing of proinsulin to insulin in the in the beta cells is impaired in DM II.

21
Q

Insulin Resistance

A

Definition: Broadly defined as a deficient biological response to normal insulin

**Leprechaunism (insulin-receptor mutations)

22
Q

Major organs affected by Insulin Resistance

A

Major organs associated with insulin resistance:

-Liver, skeletal muscle and adipose tissue

Consequences of Insulin resistance:

  • Failure to inhibit gluconeogenesis-> high fasting blood glucose levels
  • Failure of glucose uptake and glycogen synthesis -> high post-prandial blood glucose level
  • Failure to inhibit lipoprotein lipase -> FFAs -> amplify the state of insulin resistance
23
Q

Fatty Acid-Mediated Insulin Resistance

A

Insulin resistance (IR) starts in the hypothalamus -> imbalance of satiety and hunger signals

Increased inflammation and IR in adipose tissue

Excess fat released in the blood and taken up by the liver and skeletal muscles -> lipotoxicity

24
Q

Obesity and Insulin Resistance

A

Central Obesity:

-(Abdominal Fat) is often linked to insulin resistance

Inflammation

-Excess FFAs within macrophages and B cells can activate the secretion of cytokines

Free Fatty Acids (FFA):

-Excess FFAs damage B cell function-> decrease insulin secretion

Adipokines:

  • Secreted into the systemic circulation by adipose tissue
  • Deficiency of adipokines increased insulin resistance
25
Q

Linking Inflammation to Insulin Resistance

A

Hyperglycemia and dyslipidemia collectively activate pro-inflammatory mediators

Pro-inflammatory mediators cause tissue-specific inflammation by:

  • Insulin resistance in peripheral tissues
  • Impaired insulin secretion in pancreatic islets
26
Q

Clinical presentation of Diabetes

A

Asymptomatic

Polyuria, Polydipsia, nocturia, blurred vision, and, infrequently, weight loss

  • Polyuria occurs when the serum glucose concentration significantly above 180 mg/dL (10 mmol/L)
  • Glycosuria causes osmotic diuresis (i.e. polyuria) and hypovolemia -> polydipsia
27
Q

Exercise and Muscle Metabolism in Nondiabetics

A

Short-term effects:

  • Glucose cannot be transferred out of muscle to prevent hypoglycemia
  • If the exercise continues, epinephrine and norepinephrine major effect is to stimulate lipolysis

Long-term training effects:

  • Development of new muscle capillaries
  • Increased translocation of GLUT4
  • GLUT4 Promoted glucose uptake -> increase in insulin sensitivity
28
Q

Effects of Exercise in Diabetics

A

Short-term effects in Type 1 and Type 2 diabetes:

-DM I

–Well-controlled diabetics -> decrease in blood glucose

–Poorly controlled diabetics -> increases ketogenesis

-DM II: Improves insulin sensitivity as it does in nondiabetics

Long-term effects in Type 1 and Type 2 diabetes:

  • DM I: less evidence
  • DM II: Increased activity of mitochondria, increased insulin sensitivity and muscle capillary recruitment
29
Q

Chronic Complications of Diabetes

A

The morbidity associated with longstanding diabetes of either type is due to damage induced in:

  • diabetic macrovascular disease
  • diabetic microvascular disease

Macrovascular disease causes accelerated atherosclerosis in diabetics:

  • increased risk of myocardial infarction
  • stroke
  • Lower extremity ischemia

The effects of microvascular disease are most profound in the:

Retina -> diabetic retinopathy

Kidneys -> diabetic nephropathy

Peripheral nerves -> diabetic neuropathy

30
Q

Pathogenesis of Long-Term Complications of Diabetes

A
31
Q

Advanced Glycosylation End Products (AGEs)

A

Clinical significance of AGEs in diabetes:

  • Chronic hyperglycemia-> formation of AGEs
  • AGEs form irreversible cross-link with macromolecules, such as collagen-> Vascular stiffening and myocardial abnormalities

-AGEs have a role in cancers

32
Q

Type I vs Type II DM

A

Pathophys Semester II (14 decks)

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