DM Pathophys Flashcards
1
Q
Nervous system relies almost exclusively on ___ for energy
A
glucose
carbon-based, efficient fuel molecule
2
Q
Normal fasting blood glucose levels
A
70-99 mg/dL
3
Q
what is secreted in response to postprandial serum glucose changes
A
insulin
4
Q
how much of glucose from meal → stored, released later as needed by the body
A
2/3
5
Q
Falling Blood Glucose Levels, what happens to glucose metabolism
A
- Glycogen is broken down (glycogenolysis) → release of glucose
- Glucose from skeletal muscle glycogenolysis
can be used by the muscle cell but not released
into the blood - Gluconeogenesis - hepatic synthesis of glucose from AAs, glycerol, and lactic acid
- May be released into the circulation
- If normal blood glucose levels, glucose from
gluconeogenesis may be stored as glycogen
6
Q
most efficient form of fuel storage
A
Fat Metabolism
7
Q
Lipases convert TGs into ?
A
- fatty acids and glycerol
- Glycerol - can be used directly for energy, or be converted to glucose
- Fatty acids - converted to ketones by liver, then released for energy
— what results in ketone body formation (organic acids - can cause ketoacidosis)
— cannot be made directly into glucose
8
Q
can be used by the brain for energy when glucose is not available
A
Ketones
9
Q
limited facility for storage of excess amino acids
A
Protein Metabolism
Most are stored in the form of proteins manufactured by the body
10
Q
Excess amino acids can turn into what 3 products
A
fatty acids, ketones, or glucose
11
Q
what happens in protein metabolism during fasting/starving periods
A
- AAs broken down as a substrate for gluconeogenesis when glucose is not readily available
- Normally not done if sufficient glucose and insulin are present
12
Q
Secretes digestive juices into the duodenum
A
Pancreatic Acini
13
Q
Secretes hormones into the blood
A
Islets of Langerhans
14
Q
Insulin Biosynthesis and Storage
A
Produced in the beta cells in the Islets of Langerhans in the pancreas
15
Q
initially synthesized polypeptide chain during insulin biosynthesis
A
Preproinsulin
16
Q
Created by removal of signal peptide and linkage between A and B chains during insulin biosynthesis
A
Proinsulin
17
Q
active form; created by cleavage and removal of C-peptide chain during insulin biosynthesis
A
insulin
18
Q
Mature insulin molecule and C-peptides are co-stored where?
A
beta cells and released together
1. Endogenous insulin - t½ of only a few minutes (up to 15)
2. C-peptide - longer t½; can be used to assess beta cell function
19
Q
the primary regulator of beta cell secretion of insulin
A
glucose
20
Q
Glucose binds to specific cell membrane transporter proteins known as
A
GLUT
21
Q
what transports glucose into numerous body cells, including beta cells
A
GLUT-2 (and/or GLUT-1)
22
Q
what is in an inactive position until stimulated by insulin
found in skeletal muscle, adipose tissue
A
GLUT-4
23
Q
what is happening within the beta cell for insulin secretion
A
glucose is phosphorylated → ATP generation → inhibition of an ATP-sensitive K+ channel
- This channel has a receptor site that certain medications (sulfonylureas) can bind to
- Inhibition of this channel leads to depolarization of the beta cell
- Depolarization → opening of voltage-gated calcium channel → insulin secretion
24
Q
Major Actions of Insulin in Glucose Metabolism
A
- Transport - ↑ glucose transport into skeletal muscle and adipose tissue
- Synthesis - ↑ synthesis of glycogen; ↓ gluconeogenesis
25
Major Actions of Insulin in Fat Metabolism
1. Transport - ↑ transport of fatty acids into adipose cells
2. Synthesis - ↑ synthesis of fatty acid and TG synthesis
3. Breakdown - ↓ TG breakdown
26
Major Actions of Insulin in Protein Metabolism
1. Transport - ↑ transport of amino acids into cells
2. Synthesis - ↑ synthesis of proteins
3. Breakdown - ↓ breakdown of proteins
27
Major Actions of Insulin in Protein Metabolism
1. Transport - ↑ transport of amino acids into cells
2. Synthesis - ↑ synthesis of proteins
3. Breakdown - ↓ breakdown of proteins
28
Produced in the alpha cells in the Islets of Langerhans in the pancreas
Glucagon
29
major effects of Glucagon
1. Glucose Metabolism
- Synthesis - ↑ gluconeogenesis
- Breakdown - ↑ glycogen breakdown
2. Fat Metabolism
- Breakdown - ↑ adipose breakdown (activates lipase in adipose cells)
3. Protein Metabolism
- Transport - ↑ transport of amino acids into liver cells for use in gluconeogenesis
30
secreted by beta cells along with insulin and C-peptide
Amylin
31
functions of Amylin
1. Works with insulin to regulate plasma glucose concentrations
2. Decreased postprandial glucagon secretion
3. Slowed gastric emptying and increased satiety
32
secreted by delta cells in the Islets of Langerhans, as well as by other cells throughout the body
Somatostatin
33
Inhibitory hormone - suppresses release of several hormones, including insulin and glucagon
Somatostatin
34
gut-derived hormones - promote insulin release after oral nutrient load
Incretins
Accounts for ~50% of postprandial insulin secretion
Slowed gastric emptying and increased satiety
35
what hormone increases blood glucose levels during periods of stress
Epinephrine
36
how does increased EPI affect glucose
glycogenolysis in liver and muscle tissues; lipolysis in adipose tissues
37
how does decreased EPI affect glucose
release of insulin by the pancreas
38
what hormone normally inhibited by insulin and elevated glucose levels
Growth Hormone
39
Chronic hypersecretion of growth hormone affects glucose how?
insulin resistance, elevated glucose, and increased overall risk of DM
40
increased glucocorticords esp cortisol affects glucose how?
gluconeogenesis in liver
41
disorder characterized by an imbalance between insulin availability and insulin need
Diabetes Mellitus
42
where does DM rank for cause of death in US
8
$966 billion of worldwide healthcare expenditures
43
Epidemiology of DM
37 million patients in the United States
1. 90-95% have Type 2 DM; 5-10% have Type 1 DM
2. A small proportion have “other” DM (gestational, secondary)
3. Likelihood varies with age
- Patients < 20 years - 0.2%
- Patients >20 years - 12%
- Patients >65 years - 27%
44
classifications of DM
1. Type I DM - near-absence or total absence of insulin
- Related to beta-cell destruction
- Type IA DM - ~95% of T1DM - autoimmune destruction of beta cells
- Previously called “insulin dependent DM” (IDDM) and “juvenile diabetes”
2. Type II DM - associated with insulin resistance, inadequate insulin secretion, and increased glucose production
- Previously referred to as “non-insulin dependent DM” (NIDDM) or “adult diabetes”
3. Other forms (Type III) - destruction of pancreas (e.g. infiltrative disease, CF, pancreatitis), genetic defects in glucose or insulin metabolism, etc.
- Gestational DM - seen in ~7% of US pregnancies
--- 35-60% risk of development of overt DM later in life
45
Autoimmune destruction of beta cells
Associated with autoantibodies, autoreactive T lymphocytes
what type of DM
Type IA DM
~95%
46
Idiopathic
No associated autoantibodies
Most patients are of Asian or African origin
what type of DM
Type IB DM
47
cause of Type IA DM
Thought to be ⅓ due to genetics, ⅔ due to environment
1. HLA genes - contribute to 40-50% of risk of type IA DM
- 3% risk if T1ADM in mother, 6% risk if T1ADM in father
- 30-70% concordance in identical twins
2. Environmental - cow’s milk, hygiene hypothesis, certain viruses
48
what starts the active disease process and destruction of autoantibodies in Type IA DM
Genetic predisposition with an environmental trigger
- Rate of beta cell destruction varies widely
- Latent Autoimmune Diabetes in Adults (LADA) - very slow progression of type IA DM
49
Clinical s/s of type IA DM present when about what % of beta cells are destroyed
70-80%
50
describe the Process of Beta Cell Destruction
in type IA DM
1. Islets of Langerhans become infiltrated by lymphocytes
2. Exact mechanism of beta cell destruction is not fully understood
- Noted immunologic abnormalities in Type IA DM:
--- Islet cell autoantibodies
--- Activated lymphocytes in islets, peripancreatic lymph nodes, and systemic circulation
--- T lymphocytes that proliferate when stimulated with islet proteins
--- Release of cytokines within the infiltrated islets
- T cells - responsible for mediation of beta cell destruction
Immunosuppressive rx have not been significantly effective to tx T1ADM
51
what is thought to be primarily responsible for mediation of beta cell destruction
T cells
52
what is generally spared during process of beta cell destruction
Other cells in Islets of Langerhans (alpha, delta, etc.)
53
Can help make dx of type IA DM
Immunologic Markers of Type IA DM
54
MC Autoantibody to islet molecules
Anti-GAD65
autoantibodies - Positive in >85% of patients with Type IA DM
55
Limitations to Use of autoantibodies
1. Decline with increasing duration of disease
2. (+) in about 5% of pts with T2DM and gestational diabetes
3. Low IAA levels in many pts after tx with exogenous insulin
56
Insensitivity (resistance) of tissues to insulin → inadequate insulin secretion
what type of DM
Type II DM
57
for type II DM
it has Sufficient insulin in most cases to prevent _____
Not enough insulin to prevent ____
ketosis
systemic hyperglycemia
58
cause of Type II DM
Thought to have both genetic and environmental factors
1. Genetic - multiple loci associated with increased T2DM risk
- Monozygotic twins - Unaffected twin has a > 70% risk if his/her twin has T2DM
- (+) hx of T2DM in both parents - 40% risk of developing T2DM
2. Environmental - obesity, nutrition, physical activity, high/low birth wt
- #1 environmental factor - obesity (visceral)
--- >80% of T2DM pts overall - varies by ethnic group
59
common metabolic abnormalities of type II DM
1. Impaired insulin secretion and insulin resistance
2. Excessive hepatic glucose production
3. Abnormal fat/lipid and muscle metabolism
60
progression of Type II DM
1. Early - Insulin resistance = compensatory hyperinsulinemia
2. Over time - Pancreatic beta cells no longer able to maintain hyperinsulinemic state = “prediabetic” abnormalities
- Impaired glucose tolerance - higher-than-expected postprandial glucose
--- Mainly due to decreased peripheral tissue glucose uptake and use
- Impaired fasting glucose - higher-than-expected fasting glucose levels
--- Mainly due to increased hepatic production of glucose
3. As disease progresses - further decline in insulin secretion and insulin resistance contribute to consistent, worsening hyperglycemia → T2DM
61
what is The Diabetes “Triumvirate”
Previous theory of major factors contributing to poor glucose regulation in T2DM
1. Abnormal insulin secretion
2. Increased hepatic glucose production
3. Decreased peripheral glucose uptake
now thought to not be the only factors
62
what is The “Ominous Octet” of DM
New theory regarding major factors contributing to poor regulation of glucose in T2DM
1. Decreased insulin secretion - loss of pancreatic beta cell function → lower levels of insulin
2. Increased hepatic glucose production - resistance to insulin effects and lower insulin levels → loss of negative feedback stimulus to suppress hepatic gluconeogenesis
3. Decreased peripheral glucose uptake - insulin resistance and lower insulin levels → inability to absorb glucose in skeletal muscle/adipose tissue → hyperglycemia
4. Increased lipolysis - resistance to insulin’s antilipolytic effect → release of free fatty acids, which stimulate gluconeogenesis and promote further hepatic and muscle insulin resistance
- Also see ↑ insulin resistance–inducing, inflammatory, and atherosclerotic-provoking adipocytokines
- Also see ↓ insulin-sensitizing adipocytokines such as adiponectin
5. Decreased incretin effect - 2 major incretins, GLP-1 and GIP, are less effective in IFG/IGT/T2DM
6. Increased glucagon secretion - T2DM pts have increased glucagon levels and may be more sensitive to glucagon effects
- Glucagon - promotes gluconeogenesis, glycogenolysis, and lipolysis
7. Increased renal glucose reabsorption - 90% of glucose filtered in the kidney is reabsorbed in the proximal tubule by the SGLT2 transporter protein
- DM patients have been shown to have increased reabsorptive capacity
8. Neurotransmitter dysfunction - Insulin normally acts as an appetite suppressant
- High prevalence of overeating and obesity in IFG/IGT/T2DM patients despite compensatory hyperinsulinemia → suspected CNS insulin resistance
63
stimulate insulin release, inhibit glucagon secretion, promote satiety
incretins
64
Insulin resistance due to metabolic changes of pregnancy
Gestational DM
Increased risk of developing T2DM in the next 10-20 years
65
Autosomal-dominant; genetically mediated impaired insulin secretion in response to glucose
Maturity-Onset Diabetes of the Young
66
how can genetic defect cause forms of DM
mutant insulins or insulin receptors
abnormal mitochondrial DNA
abnormal formation of part or all of the pancreas
67
what can cause secondary DM
1. Hormonal tumors - acromegaly, Cushing, glucagonoma, pheochromocytoma
2. Liver disease - cirrhosis, hemochromatosis
3. Pharmacologic agents - corticosteroids, thiazides, beta blockers, antipsychotics
4. Pancreatic disease - pancreatitis, pancreatectomy, CF, infiltrative disease
68
increases risks of metabolic syndrome
1. atherosclerosis
2. heart disease
3. stroke
4. cancer
5. dementia
6. type 2 DM
7. erectile dysfunction
69
criteria for metabolic syndrome
3+ of the following:
1. Waist circumference: > 40 in (102 cm) in men, >35 in (88 cm) in women
2. Fasting triglycerides: >150 mg/dL, or on medication
3. HDL cholesterol: <40 mg/dL (men), or <50 mg/dL (women), or on medication
4. Bp: >130 mm systolic or >85 mm diastolic, or on medication
5. Fasting plasma glucose: ≥100 mg/dL, or on medication
Also associated with - small, dense LDL; hyperuricemia; prothrombotic state; proinflammatory state; PCOS; NAFLD
70
epidemiology of MetS
1. Overall prevalence in US - 22% of pts (43% of pts 60+)
2. Varies by ethnicity
- Highest risk - Mexican Americans, Blacks
3. W>M
71
risk factors for MetS
1. Overweight/Obesity - central (upper body) obesity, visceral obesity linked to higher risk
- Can still manifest in patients with normal weight
2. Physical Inactivity - associated with increased risk of obesity, lower HDL, higher TG, higher BP, and higher glucose
- > 4 hours TV/computer per day = 2x increase in metabolic syndrome risk
3. Aging - Increased prevalence in pts >50 (nearly 50%)
4. T2DM - ~75% of IGT/T2DM pts meet MetS criteria
- Higher rates of CV disease than T2DM pts who do not have MetS
5. CV Disease - 50% of CHD pts meet MetS criteria
- Includes ~35% of pts with premature (< 45 y/o) CAD
- MC in women with CV disease
6. Lipodystrophy - associated with increased prevalence of MetS
72
causes of MetS
1. Insulin Resistance - primary contributor
- Increased circulating free fatty acids → further reduction of antilipolytic effect of insulin
- Leptin resistance - thought to also play a role
2. Glucose Intolerance - increased levels of postprandial and fasting glucose
3. HTN - insulin resistance leads to loss of insulin’s normal vasodilatory effect, without impacting its mild sodium retention effect
4. Waist Circumference - increased visceral adipose tissue → greater effect of circulating free fatty acids on hepatic metabolism
5. Dyslipidemia - influx of free fatty acids to liver → abnormal lipid production
- Triglycerides - increased rate of production
- HDL - decreased cholesterol content and increased clearance of HDL from circulation
- LDL - increased rate of small, dense LDL particles
6. Proinflammatory cytokines - increased production due to the increased overall mass of adipose tissue
- Includes IL-1, IL-8, IL-16, TNF-alpha, C-reactive protein
7. Adiponectin - Reduced rate of production in pts with metabolic syndrome
73
what hormone reduces appetite, and promotes insulin sensitivity
Leptin
74
what also contributes to HTN through activation of the RAAS
hyperuricemia
75
what is an anti-inflammatory cytokine produced exclusively by adipocytes
Adiponectin
76
manifestations of MetS
Typically not associated with any major or “classic” s/s!
1. Common s/s
- increased waist circumference
- HTN
2. Acanthosis nigricans - velvety darkening of skin folds associated with insulin resistance
3. Hepatic enlargement - possible if “fatty liver” (NAFLD/steatohepatitis) is present
4. Hyperuricemia - may rarely present with an episode of gouty arthritis
5. Polycystic ovarian syndrome - may see constellation of infertility, menstrual irregularities, obesity, and hirsutism
6. Obstructive sleep apnea - commonly associated with obesity, HTN
77
manifestations of MetS
Typically not associated with any major or “classic” s/s!
1. Common s/s
- increased waist circumference
- HTN
2. Acanthosis nigricans - velvety darkening of skin folds associated with insulin resistance
3. Hepatic enlargement - possible if “fatty liver” (NAFLD/steatohepatitis) is present
4. Hyperuricemia - may rarely present with an episode of gouty arthritis
5. Polycystic ovarian syndrome - may see constellation of infertility, menstrual irregularities, obesity, and hirsutism
6. Obstructive sleep apnea - commonly associated with obesity, HTN
78
tx for MetS
Primary Approach - Wt reduction
1. Diet - restriction of ~500 kcal/day
- Low-carb diets - more rapid initial wt loss, but equal to low-cal after 1 yr
- Encourage high-quality diet overall - vegetables, lean proteins, whole grains
2. Physical Activity - At least 30 min/day
- 60-90 min/day typically needed for significant weight loss
- May need cardiovascular evaluation before starting exercise routine
- May improve visceral fat loss in particular
3. Other Interventions - anti-obesity drugs, bariatric surgery, support groups
4. Dyslipidemia
- restrict dietary cholesterol
- Statins - if (+) DM, (+) CVD, high 10-yr CVD risk
- Fibrates - may be considered to help reduce triglycerides
5. HTN
- sodium-restricted diet
- home BP monitoring, ACE or ARB rx
6. Hyperglycemia
- reduced dietary carbs
- TZDs and/or metformin
