Diabetes Mellitus Pathophysiology and pharmacology

Endo week 1

2 main function of pancreas

Make enzymes involved in absorption and make hormones involved in glucose homeostasis

Exocrine pancreas secretes what

pancreatic juice into the duodenum

Endocrine pancreas

consists of islets of Langerhans that secretes insulin and other hormones

glucagon and proglucagon

Alpha cells in Pancreatic Islets secrete

Amylin

creates full feeling, delays gastric emptying, and inhibits glucagon

Insulin, C-peptide, proinsulin, amylin

Beta cells in Pancreatic Islets secrete

Glycogenolysis

The breakdown of glycogen to glucose in the liver

Glycogenesis

Process of glycogen synthesis

Glyconeogenesis

Formation of glucose from non-carbohydrates and fat

Liver

Where does gluconeogenesis typically occur

glucagon release

Low blood sugar promotes

Stimulates glycogen breakdown

Glucagon does what

Raises blood sugar

Glycogen breakdown does this

Lipogenesis

formation of fat

Lipolysis

Breakdown of lipids

Increase

Insulin effect on liver - glucose uptake

Decrease

Insulin effect on liver - Glucose output

Decrease

Insulin effect on liver - gluconeogenesis

decrease

Insulin effect on liver - glycogenolysis

increase

Insulin effect on liver - lipogenesis

increase

Insulin effect on liver - glycogenesis

increase

Insulin effect on Adipose tissue - glucose uptake

increase

Insulin effect on Adipose tissue - lipogenesis

decrease

Insulin effect on Adipose tissue - lipolysis

increase

Insulin effect on Skeletal muscle - glucose uptake

increase

Insulin effect on Skeletal muscle - glycogenesis

increase

Insulin effect on Skeletal muscle - protein synthesis

glycogenolysis, gluconeogenesis, conversion of fatty acids and amino acids to keto acids

Insulin in liver inhibits

Insulin in liver promotes

Anabolic actions, storage of glucose as glycogen, glucokinase, glycogen synthase, inhibit glycogen phosphorylase, triglyceride synthesis, VLDL formation

Glycogenolysis

glycogen into glucose

High blood sugar promotes insulin release in which cells

Pancreatic beta

Low blood sugar promotes glucagon release in which cells

Pancreatic alpha

Glucose

Insulin

Fatty acids

Glucagon

Dietary carbohydrate

Dietary lipids

Fatty acids

glucagon

Insulin

Effects of insulin in muscle

Increased glycolysis and increased protein synthesis

Increases glucose transport, induces glycogen synthase, inhibits glycogen phosphorylase

How does insulin in muscle increase glycogenesis

How does insulin in muscle increase protein synthesis

Increases amino acid transport and increases ribosomal protein synthesis

Effects of insulin in adipose tissue

Increased triglyceride storage, inhibition of intracellular lipase

Lipase

Catalyzes the hydrolysis of lipids

How does insulin in adipose tissue increase triglyceride storage

LPL is activated to hydrolyze triglycerides from lipoproteins into fatty acids which are moved into the cell

Glucose transport into cells provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport

Where are insulin receptors found

Membranes of liver, skeletal muscle, and adipose tissue

Glucokinase in pancreatic beta cell

catalyzes the rate limiting step in glucose metabolism

Mechanism of insulin secretion by pancreatic beta cell

Glucose enters cell through GLUT then is catalyzed into glucose-6-phosphate by glucokinase then pyruvate then pyruvate enters the mitochondria to create atp/adp which closes the ATP sensitive potassium channel which depolarizes and opens the voltage dependent calcium channel. Ca then interacts with cAMP, and secretory granules exit the cell when incretins act on their receptor that potentiates after a meal

example of incretin

GLP1

Prediabetes

used to identify glucose or A1C levels that do not meet the criteria for diabetes yet fall in an intermediate range between normoglycemia and diabetes

Diabetes mellitus

Elevated glucose associated with absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action

Categories of Diabetes

Type 1, type 2, Gestational, Specific

Monogenetic diabetes syndromes

Neonatal diabetes, Maturity Onset Diabetes of the Young (MODY)

Types of diabetes due to causes other than 1, 2, or gestational

Monogenetic diabetes syndromes, diabetes in the context of disease of the exocrine pancreas, drug or chemical induced

Examples of drug or chemical induced diabetes causes

Glucocorticoid use, HIV treatment, post-transplantation, systemic anti-cancer therapy

A1C

Indirect measure of average blood glucose levels based on the attachment of glucose to hemoglobin

Advantages of A1C test

No fasting required, less daily disturbances/representation for roughly 3 months, greater preanalytical stability

Disadvantages of A1C test

Lower sensitivity at designated point, limited availability, imperfect correlation between A1C and average glucose in certain individuals

Examples of when average glucose and A1C may be inaccurate

anemia, erythropoietin treatment, hemodialysis or HIV treatment

FPG stands for

Fasting Plasma Glucose Test

FPG

checks fasting blood glucose levels and measures blood glucose at a single point

OGTT stands for

Oral Glucose Tolerance Test

OGTT, 2-h PG

Measures blood glucose before and after drinking a 75g glucose drink. Requires fasting

OGTT is used to diagnose what

GDM at 24-28 wks

GDM stands for

gestational diabetes mellitus

OGTT one step strategy

75g OGTT - fasting

Two step OGTT

1. 50g GLT - non-fasting

2. 100g OGTT - fasting

Random plasma glucose test

Blood check at any time of the day. Usually for severe diabetes symptoms

Diabetes A1C

greater or equal to 6.5

Fasting Plasma Glucose Diabetes Diagnosis

greater or equal to 126

Diabetes 2 hour PG during OGTT

greater or equal to 200

Prediabetes A1C

5.7-6.4

Prediabetes FPG

100-125

Prediabetes 2hr PG during 75g OGTT

140-199

Prediabetes Random plasma glucose test

N/A

Type 1 diabetes has what

Destruction of B cells/reduced insulin production

Type 2 diabetes has what

Reduced insulin production and insulin resistance

Types of Type 1 Diabetes

1a and 1b (idiopathic)

Type 1 DM mechanism

CD4+ helper T cells identify and the CD8+ T cells mistakenly attack and destroy insulin-producing beta cells

Insulin replacement therapy in diabetes mellitus

type 1 need to live. type 2 may benefit but might not need to survive

Interruption of insulin replacement therapy for Type 1 DM

Diabetic ketoacidosis or death

Diabetic ketoacidosis

Insulin deficiency leads to cells not getting glucose so cells create ketones by burning fat

Early symptoms of Diabetic Ketoacidosis

Thirst/dry mouth

frequent urination

high blood glucose

high ketone levels in urine

Later symptoms of diabetic ketoacidosis

Constant tiredness

dry skin

nausea/vomiting/abdominal pain

difficulty breathing

fruity odor on breath

confusion/difficulty paying attention

Type 2 DM is characterized by

Relative deficiency in insulin secretion combined with tissue resistance to insulin action

Consequences of pancreatic beta cell to glucose sensitivity impairment

Blood glucose rises in excess after meals and liver glucose is released during fasting

Patients can have elevated levels of fasting insulin because

Higher fasting glucose, insulin resistance, increased amounts of proinsulin

Insulin resistance

Failure of normal amounts of insulin to elicit the expected response

Dysfunctional liver metabolism due to

insufficient insulin secretion and excessive glucagon secretion

Dysfunctional liver glucose in fasting state

too high glucose output

Dysfunctional liver glucose after meals

Glucose output inadequately suppressed

Factors influencing insulin resistance

obesity, activity level, aging

Why does obesity impact insulin resistance

increased resistance in liver and skeletal muscle. Insulin promotes weight gain due to lipogenesis in adipose tissue and liver

HHNS stands for

Hyperosmolar hyperglycemic Nonketotic Syndrom

HNSS

life-threatening condition that occurs when T2DM is poorly managed

Symptoms of HHNS

Dry, parched mouth

extreme thirst

warm, dry skin that does not sweat

high fever

sleepiness or confusion

loss of vision

hallucinations

weak on one side of the body

Gestational diabetes mellitus

Placenta and placental hormones create an insulin resistance leading to abnormal glucose levels in the second and third trimester

General symptoms of diabetes

Increased urination and thirst, feeling very hungry even if eating, extreme fatigue, blurry vision, cuts or bruises that are slow to heal