Type 1 & Type 2 Diabetes Flashcards
What are the 2 metabolic pathways?
1) Anabolic pathways:
* synthesis of large molecules from small molecules (e.g. protein and glycogen synthesis)
* require energy (ATP)
2) Catabolic pathways:
* break down of large molecules to small molecules
* release energy (ATP) e.g. respiratory chain; oxidative
phosphorylation
Anabolic hormones:
build fuel stores (insulin, growth
hormone)
Catabolic hormones:
break down fuel stores (glucagon, cortisol, epinephrine)
Glucose is the circulating form.
What is the storage form & major storage site?
glycogen
liver
Fatty acids are the circulating form.
What is the storage form & major storage site?
triglycerides
adipose tissue
Amino acids are the circulating form.
What is the storage form & major storage site?
proteins
muscle
What is the absorptive (fed) state?
period after meal that food is digested (4-5 h)
What is the Post-absorptive (fasting) state?
inter-digestive period that begins 5-6 h after meal
What is the short and long fasting states states of Post-absorptive (fasting state)?
Short fasting:
Gluconeogenesis - The formation of glucose from non-hexose precursors
Long fasting:
- go to fatty acid ketones
- blood & liver
Plasma glucose is tightly regulated by hormones:
- insulin, glucagon, epinephrine: fast acting (minutes)
- cortisol, growth hormone: long acting (hours)
Normal plasma glucose:
3.9-8.3 mM (70-150 mg/dl)
What is interesting about the brain?
- DEPENDENT on GLUCOSE as a PRIMARY energy
source (capable of using ketones e.g. fasting) - can NOT synthesize glucose
- can NOT store glycogen
What is the #1 tissue affected when blood glucose is reduced?
BRAIN (b/c dependent on glucose as primary energy)
What is the endocrine pancreas and what is each islet?
- Endocrine pancreas:
- 1-3% of total weight
- 0.5-1 x 106 islets
- Each islet:
- 50-500 μm diameter
- 2000-4000 cells
β-cells (∼70%):
insulin, amylin
α-cells (∼25%):
glucagon
δ-cells (∼5%):
somatostatin
PP cells:
Pancreatic polypeptide
What is Somatostatin?
- found in islets (also hypothalamus, gut, stomach)
- released in response to nutrients (e.g. glucose)
- inhibitory actions on many tissues
What is Islet amyloid polypeptide (IAPP; amylin)?
- co-secreted with insulin
- inhibits gastric emptying
- decreases appetite
- forms islet amyloid deposits in T2D
What is Pancreatic polypeptide?
- vagal activation stimulates its secretion
- physiological role unclear - likely inhibits pancreatic
exocrine secretion
Islets are ____ ______
heavily vascularized
Blood flow within the islet is from ___-cells to ___-cells
β
α
Islets innervation:
Both sympathetic and parasympathetic fibers
What is the structure of insulin?
● insulin is a 6 kDa peptide
● consists of 2 chains:
A-chain → 21 amino acids
B-chain → 30 amino acids
● A-chain and B-chain are linked by DISULFIDE BONDS
● Basic structure is highly conserved in most species e.g. beef → 2 aa pork → 1 aa
What is the synthesis process of insulin?
(synthesized in the:) rough endoplasmic reticulum
↓
Proinsulin
↓
proinsulin (9 kDa)
↓
Golgi apparatus
↓
insulin granules
↓
insulin and C-peptide
Proinsulin has __% of the bioactivity of insulin
<5&
(is much less - therefore not as effective as mature insulin)
What is the C-peptide?
involved in proinsulin processing
- secreted in equimolar amounts with insulin
- marker of insulin secretion from β-cells in diabetic patients
- biological action is not clear
How is insulin secretion regulated?
(B-cell)
stimulated by:
- nutrients (GLUCOSE, AA’s, ketones)
- GI hormones (released after meal - GIP, GLP-1)
- islet hormones (glucagon)
- increase PNS
inhibited by:
- somatostatin
- increase SNS
- prolonged glucose + FFA (toxic can lead to destruction)
As [glucose] increases, insulin secretion ___
increases
What is the cellular mechanism of insulin secretion?
glucose –(glucose transporter)–> glucose –(glucokinase)–> G-6-P –> increase ATP –(inhibit)–> ATP-dependent K+ channel –> membrane depol. –(stimulate)–> voltage-gated Ca2+ channel –(stimulate)–> increase Ca2+ –(insulin vesicles)–> insulin
Insulin receptor is a _____ composed of two α- and β-subunits and acts as an ____ (tyrosine kinase)
glycoprotein
enzyme
Insulin has __ _____ _____proteins
NO plasma carrier
Insulin has NO plasma carrier proteins
Therefore, it has ____ plasma half-life (___ min)
SHORT
3-5 min
∼___% of insulin is removed during ___ pass through ___
~50%
1st
liver
Describe the biological effects of insulin
↓ Insulin, causes ↓ glucose
What are the major target tissues for insulin?
- skeletal muscle
- adipose tissue
- liver
Insulin ___ glucose uptake in ____ and ____ ____ by regulating glucose transporter (GLUT_)
↑
muscle and adipose tissue
4
Glucose transporter in LIVER (GLUT _) is ___ regulated by insulin
2
NOT
What is the most important hormone in ↑plasma glucose?
glucagon
What is glucagon?
- Glucagon is a single chain polypeptide (29 amino acids)
- Molecular weight: ∼ 3.5 kDa (small peptide)
α cells –> proglucagon –prohormone convertase 2 –> glucagon
What happens when glucagon attaches to the glucagon receptor?
G-protein activates Adenylate cyclase –> ATP–>cAMP –> cAMP-dependent protein kinase A –> biological effects
What is the regulation of glucagon secretion?
Stimulated by:
- nutrients (decrease glucose, AA’s)
- hormones: GIP
- increase PNS, increase SNS
Inhibited by:
- nutrients (increase glucose, FA’s)
- hormones (somatostatin, GLP-1)
What is the role of glucagon in glucose regulation?
- Glucagon OPPOSES the metabolic actions of insulin
- The major site of action: LIVER
- Important metabolic effects of glucagon in the liver:
- Carbohydrates
- Fat
- Protein
What is the regulation of blood glucose by insulin & glucagon?
- Insulin ↓ plasma glucose by promoting glucose UPTAKE & its STORAGE
- Glucagon ↑ plasma glucose by increasing liver GLUCOSE OUTPUT
Glucocorticoids – Cortisol (hormone in regulation of carbohydrate metabolism)
- counter-regulatory to insulin action
- contributes to maintenance of plasma glucose levels during FASTING
- mechanism: increase hepatic GLUCONEOGENESIS (counteracts insulin)
Catecholamines – Epinephrine (hormone in regulation of carbohydrate metabolism)
- mobilizes glucose stores
- decreases glucose uptake by liver
- inhibits insulin production
Glucagon-like peptide-1 (GLP-1) (hormone in regulation of carbohydrate metabolism)
- an incretin hormone released by small intestine
- stimulates insulin release from β-cells
- promotes β-cell proliferation
- suppresses glucagon release
- slows gastric emptying and glucose absorption
- stimulate satiety centre
Growth hormone (hormone in regulation of carbohydrate metabolism)
- antagonizes insulin effect
- inhibits insulin action
- decreases glucose uptake
Primary β-cells occasionally ____.
replicate
In a normal person there is a ____ BALANCE between
β-cell replication and β-cell death.
TIGHT
Any factor that INCREASES the RATE of β-cell DEATH will cause ______.
diabetes
What is Diabetes Mellitus?
Diabetes is a chronic metabolic disorder characterized by hyperglycemia resulting from IMPAIRED INSULIN SECRETION and/or ACTION.
- Diabetes = “siphon” or “running through”
- Mellitus = sweet
What is the MOST common endocrine disorder?
diabetes mellitus
What is the prevalence of diabetes?
- ~463 million people suffer from diabetes in the world
- Over 2 million Canadians have diabetes
- Currently, 1 in 3 Canadians has diabetes or prediabetes
- Diabetes contributes to death of >40,000 Canadians per year
- Financial burden of diabetes and its complications is about $3.6 billion/year in Canada
What is the mechanism of hyperglycemia in diabetes?
- Absolute (T1D) or relative (T2D) insulin deficiency
1) Increase in hepatic glucose output
2) Decrease in glucose uptake
Type 1 diabetes:
- juvenile onset, ketosis-prone diabetes
- previously named INSULIN-DEPENDENT diabetes mellitus
(IDDM) - usually occurs <30 years
- incidence: ~1:250
- 10% of diabetic cases
- due to AUTOIMMUNE destruction of β-cells
- involves both GENES and ENVIRONMENTAL factors
T1D is an autoimmune disease:
- T lymphocyte infiltration of islet (INSULITIS)
- Several circulating islet cell ANTIBODIES (ICAs) against β-cell proteins (e.g. insulin, GAD) are produced
- Associated with other autoimmune diseases (e.g. Hashimoto’s thyroiditis)
T1D has an environmental component:
- Viruses associated with T1D (e.g. coxsackie virus B4, mumps, rubella)
- Diet associated with T1D (e.g. infants fed cow milk)
T1D has genetic component:
- Many GENETIC loci associated with T1D were identified
- Close association with major histocompatibility complex (MHC) class II
- MHC genes encode human leukocyte antigens (HLAs) => presentation of antigens to the immune system
- HLA-DR or HLA-DQ alleles can predispose or protect e.g. HLA-DR4 => ~10X increase risk
What are possible triggers of autoimmunity in T1D?
- Molecular mimicry:
Immune system by mistake attacks β-cell proteins
that share structural similarity with foreign antigen. - Bystander activation:
Islet inflammation stimulates activation of β-cell
specific T cells (e.g. viral infections) - beta-cell apoptosis:
- environmental trigger of β-cell death (e.g. virus) - phagocytosed by antigen presenting cells (APCs) - present β-cell antigens to immune system
- initiate immune response
Role of T cells in β-cell destruction in T1D:
- Both CD4+ (helper) and CD8+ (cytotoxic) T cells are involved
- T cells that recognize β-cell antigens (e.g. GAD, insulin) are
found in islets during T1D - β-cell specific CD8+ cytotoxic T cells are the major cell type contributing to β-cell death in T1D
Type 2 diabetes:
- Adult-onset, ketosis-RESISTANT diabetes
- Previously called non-insulin-dependent diabetes
(NIDDM) - Typically patients are >45 years
- Increasing in children (associated with obesity)
- Incidence: 1 in 20
- 90-95% of diabetic cases
- Symptoms can be absent or minimal (SLOW ONSET)
- Patients are usually OVERWEIGHT (70-80%)
Genetic and environmental factors both contribute to pathogenesis of T2D:
- Genetic component:
- about 100% concordance in monozygotic twins
- frequent in certain ethnic groups
- Environmental component:
- associated with sedentary life style and high fat
Multiple genes are involved in pathogenesis of T2D:
Rare single gene mutations:
- insulin receptor
- mitochondrial DNA
- proinsulin
- prohormone convertase 1
- leptin
- PPAR (peroxisome proliferator-activated receptor)
- Mature onset diabetes of the young (MODY), autosomal dominant, early onset T2D
T2D is associated with defects in…
BOTH insulin action (↑insulin resistance) and insulin secretion
Early diabetes:
“impaired glucose tolerance (IGT)”
* abnormal OGTT but normal fasting glucose
* treated with diet and exercise
Overt, but mild, diabetes:
- moderate fasting hyperglycemia (∼7 mM)
- insulin resistance present
- insulin secretion present but insufficient
- treat with exercise, diet, oral hypoglycemic drugs
Advanced diabetes:
- severe fasting hyperglycemia (>9 mM)
- insulin secretion greatly impaired (β-cell failure)
- patients often require insulin therapy
What are possible causes of progressive B-cell failure in T2D?
- Glucolipotoxicity:
Prolonged exposure to high levels of glucose and free fatty acids is toxic to β-cells - β-cell exhaustion:
Islet β-cells become “exhausted” in the presence of increasing insulin resistance and hyperglycemia. - Islet amyloid deposits:
Toxic amyloid deposits formed by aggregation of islet amyloid polypeptide (IAPP; amylin) are found in most patients with T2D - Islet inflammation:
Growing evidence suggests that islet inflammation plays a key role in pathogenesis of T2D
In healthy individuals ∼50% of total daily insulin is secreted during ___ periods, which suppresses lipolysis, proteolysis, and glycogenolysis.
BASAL
The remainder of insulin secretion is postprandial. Insulin is released from islet β-cells in a ______ manner in response to ______ arterial _____ concentration.
biphasic
increased
glucose
1st phase consists of a ____ spike lasting ∼10 min followed by 2nd phase, which reaches _____ at 2–3 hrs.
brief
plateau
In response to a meal, there is a _____ release of pre- formed insulin stored in β-cell granules.
RAPID
This “first phase” of insulin release ____ peripheral use of prandial nutrients, inhibits hepatic glucose production, thereby limits postprandial glucose increase.
promotes
The first-phase insulin secretion BEGINS WITHIN 2 ____ of nutrient ingestion and continues for 10 to 15 minutes.
minutes
The second phase of prandial insulin secretion follows, and is sustained until ______ is restored.
normoglycemia
It is widely believed that _____ first and second phase insulin release are ____ in patients with T2D.
BOTH
impaired
Evidence suggests that impaired insulin release in T2D occurs:
- at early stages of diabetes
- precedes insulin resistance
- represent primary genetic risk factor predisposing
to T2D
The number of islet resident _____ is ELEVATED in pancreatic islets from patients with T2D
macrophages
Chronic inflammation in T2D:
● Islet amyloid formation is a pathologic characteristic of patients in T2D.
● Islet amyloid is formed by aggregation of the β-cell hormone islet amyloid polypeptide (IAPP) or amylin.
● Amyloid formation contributes to islet inflammation in patients with T2D.
_____ formation contributes to islet inflammation in patients with T2D.
amyloid
What is the proposed role for Fas receptor in β-cell death in T2D?
- Normal β-cells do not express cell death Fas receptor at detectable levels.
- β-cells normally do express Fas ligand.
- Expression of Fas receptor is up-regulated in β-cells in conditions that cause β-cell stress such as exposure to cytokines or elevated glucose.
Progressive LOSS of pancreatic __-cells is the major problem in both T1D and T2D although the underlying mechanisms are different.
β
β-cell apoptotic factors in T1D and T2D:
- high glucose
- high FFAs
- cytokines
- islet amyloid (only T2D)
- damage of exocrine pancreas
What is the main risk factor for T2D (slide 71 has all)
overweight or obesity (ABDOMINAL obesity)
(**increase risk if you have this over someone else)
What is the diagnosis of diabetes?
- Fasting plasma glucose (FPG) ≥7.0 mmol/L Fasting: no caloric intake for at least 8 hours
- A1C ≥6.5% (in adults)
- 2 h plasma glucose (PG) in a 75 g OGTT ≥11.1 mmol/L
OGTT: oral glucose tolerance test - Random PG ≥11.1 mmol/L
Random: any time of the day, without regard to the interval since the last meal
In the ABSENCE of symptomatic HYPERGLYCEMIA, if a SINGLE LAB TEST result is in the diabetes range, a _____ confirmatory lab test (FPG, A1C, 2hPG in a 75 g OGTT) MUST be done on another day.
repeat
*need 2 measurements on 2 diff. days for confirmation of diabetes
What are the acute complications of diabetes?
- glucosuria: glucose appears in urine
- polyuria: frequent urination
- polydipsia: excessive thirst
- polyphagia: excessive food intake
- ketoacidosis
↓insulin→↑lipolysis→↑fatty acids→liver→ketones
What are chronic complications of diabetes?
- Neuropathy:
- loss of sensation due to damage of
nerve fibers (e.g. heat, cold, pain) - high blood glucose changes the metabolism of nerve cells
- reduced blood flow
- Nephropathy:
- has a slow onset
- may result in severe kidney failure
- patients may need dialysis or kidney transplant
- Cardiovascular disease: - atherosclerosis
- high blood pressure
- myocardial infarction
- Retinopathy: damage of retina
- Cataract: damage of lens
- Both may cause BLINDNESS
Treatment strategies for T1D:
Insulin therapy
* patients with T1D need exogenous insulin
* insulin can not be administered orally
* insulin preparations:
porcine, bovine & **recombinant human insulin
* inhaled powder insulin
Who discovered insulin?
Drs Banting & Best (took out dog’s pancreas - became diabetic)
a kid with T1D was underweight and then a year later with insulin therapy gained weight b/c insulin is a growth factor as well
What is an advantage & disadvantage of Islet transplantation in T1D?
- Advantage: provides an ENDOgenous source of insulin
- Disadvantage: requires life-time immunosuppressive therapy
What are the treatment strategies for T2D?
- START with DIET modifications and exercise for weight loss (weight loss+ regular exercise:↓risk of progression).
- If not effective, treat with oral anti-hyperglycemic agents (e.g. metformin).
- If blood glucose is not controlled by oral agents, insulin therapy is needed.
- Individualize therapy choice based on characteristics of the patient and the agent.
- Choose initial therapy based on blood glucose level.
- Reach target within 3-6 months of diagnosis.
What is Gestational diabetes?
- It develops during pregnancy
- Typically occurs in week 24 - 28 of gestation
- Higher risk of developing T2D in future
- Physiological state of insulin resistance requiring higher
insulin levels during pregnancy - Placental hormones provoke ↑blood glucose which can affect
growth and welfare of baby - Most cases are asymptomatic
- Resolves after pregnancy
What are complications of gestational diabetes for the mother?
- high blood pressure
- pre-eclampsia (a serious complication of pregnancy
that can threaten lives of both mother and baby) - major symptoms:
- hypertension
- proteinuria (protein in urine) - edema of hands and feet
- risk of future gestational diabetes or T2D
What are complications of gestational diabetes for the baby?
- excessive birth weight (macrosomia)
- early (preterm) birth and respiratory distress syndrome
- low blood glucose (hypoglycemia)
- seizures (due to severe episodes of hypoglycemia)
- risk of T2D later in life
Insulin excess is characterized by _______
HYPOglycemia (↓blood glucose levels)
What are common causes & major symptoms of hyperinsulinemia?
- Common causes:
- high dose of insulin
- β-cell tumors
- Major symptoms:
- depressed brain function
- unconsciousness
- death
What is the Dawn Effect?
- RISE in the BLOOD GLUCOSE in early morning caused by counter-regulatory hormones.
- Leads to ELEVATED FASTING blood glucose (FBG) in T1D and T2D patients.
- Results in body needing MORE INSULIN in early morning.
- Detected by SELF-MONITORING blood glucose (SMBG) at EARLY morning (2-3 am).
