Diabetes Mellitus Flashcards
2.4
what is diabetes mellitus
Group of metabolic disorders sharing the common Hyperglycemia.(defects in insulin secretion, insulin action or both.)
* Metabolic derangement associated with secondary damage in multiple organs -
kidneys, eyes, nerves & blood vessels.
what have contributed to the
increases in diabetes and obesity, also know as Diabesity epidemic
Increasingly sedentary lifestyles and poor eating habits
define prediabetes
elevated blood sugar that does not reach the criterion accepted for an outright diagnosis of
diabetes
Diagnostic criteria for:
Diabetes Mellitus
➢Random blood glucose concentration >200 mg/dL
➢Fasting blood glucose concentration greater than 126 mg/dL
➢Oral glucose tolerance test (OGTT)
➢Glycated hemoglobin(HbA1c)>6.5%
- A fasting plasma glucose between 100 and 125 mg/dL and/or
- A 2-hour plasma glucose between 140 and 199 mg/dL during an OGTT test, and/or
- HbA1C level between 5.7% and 6.4%
is termed as:
Impaired glucose tolerance (prediabetes)
Pathogenesis of Type I DM
- Autoimmune disease islet destruction is caused primarily by T cells reacting against endogenous β-cell antigens.
“insulin-dependent diabetes mellitus” is what type of DM
- Absolute lack of insulin *
TYPE 1 DM
TYPE 1 DM accounts for _________-% of cases
5-10%
TYPE ____DM Develops in childhood and peaks at puberty
type 1 DM
_____ and ______ – late in course of illness ( >90% β cell loss) for type 1 DM
Ketoacidosis and coma
genetic susceptibility of type 1 DM: HLA
✓HLA: Strongest association class II MHC coded on Chr 6p21 (HLA-DR3 and DR4)
genetic susceptibility of type 1 DM: NON-HLA
Insulin gene- reduced expression in thymus & reduced elimination of self reactive T cells
CTLA4 + PTPN22 ==> inhibit T cell response
genetic susceptibility of type 1 DM: NON-HLA
Insulin gene- reduced expression in thymus & reduced elimination of self reactive T cells
CTLA4 + PTPN22 ==> inhibit T cell response
loss of self tolerance lead to __________- against a variety of beta cell antigens, including insulin and the beta cell enzyme glutamic acid decarboxylase detected in
70-80% patients
autoantibodies,
loss of self tolerance lead to __________- against a variety of beta cell antigens, including insulin and the beta cell enzyme glutamic acid decarboxylase detected in
70-80% patients
autoantibodies,
what are Initiating triggers for Type 1 DM
Mumps, Rubella & Coxsackie B viruses - Molecular mimicry to β cell antigens
what are Intestinal dysbiosis for type 1 DM
Change in GUT flora ? Cause or effect of hyperglycemia
determine if APS1 or APS2
- Mutations in the autoimmune regulator (AIRE) gene - chromosome 21q22.
- In the absence of AIRE function, central T-cell tolerance to peripheral tissue antigens is
compromised, promoting autoimmunity.
APS1 or APECED (Autoimmune polyendocrinopathy, candidiasis, & ectodermal dystrophy)
describe APS2
- starts in early adulthood
- combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes
describe APS2
- starts in early adulthood
- combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes
determine if type 1 or type 2 DM:
Accounts for 90% to 95% of diabetic cases
multifactorial complex disease.
interactions of genetics, environmental risk factors, and inflammation
Primary defect
❖ Insulin resistance:
- derrangement of B cell secretion
type 2 DM
describe what insulin resistance
decreased response of peripheral tissues to insulin
-Insulin resistance predates hyperglycemia and is accompanied by compensatory beta cell
hyperfunction and hyperinsulinemia in the early stages
environmental factors of type 2 DM
sedentary Life style, dietary habits, obesity.
insulin resistance :
Failure to inhibit endogenous glucose production (____________) in the liver, which
contributes to _____________ blood glucose levels
gluconeogenesis , high fasting blood glucose
insulin resistance :
Abnormally low _____________ and ________- synthesis in skeletal muscle following a meal, which contribute to a high ____________-blood glucose level
low glucose uptake, and glycogen
postprandial
insulin resistance :
Failure to inhibit hormone-sensitive______ in adipose tissue, leading to excess circulating __________ - insulin resistance
lipase ,free fatty acids (FFAs)
insulin resistance :
Failure to inhibit hormone-sensitive______ in adipose tissue, leading to excess circulating __________ - insulin resistance
lipase ,free fatty acids (FFAs)
what is the Direct role of FFA :
Excess FFA are taken up in muscle and liver leading to increased intracellular triglyceride ____________ (acquired insulin resistance state)
potent inhibitors of insulin signaling
what is the Indirect ( Inflammatory Cytokines) role of FFA :
Excess FFAs within macrophages and beta cells activate the inflammasome (multiprotein cytoplasmic complex) that leads to secretion of the cytokine ________ that promotes insulin resistance
interleukin IL-1β
list the mechanisms of B cell dysfunction
- Excess FFA
- Chronic hyperglycemia
- Amyloid replacement in >90% islets (?cause / effect)
End result: by inadequate insulin secretion
Adiponectin levels _____ in obesity – insulin resistance
decreased
____________ release of hormones from adipocytes in relation to metabolic state
Adipokine Cytokines:
Thiazolidinediones (TZD) are synthetic ligands of _______ decreases insulin resistance.
PPAR gamma (Peroxisome proliferator-activated
receptor gamma (PPARγ
Effect of prolonged Insulin resistance in type 2 DM
* initial stages compensatory B cell hyperactivity leads to
hyperinsulinemia – euglycemic
Effect of prolonged Insulin resistance in type 2 DM* Inability for long term adaptation leads to
- insulin deficiency
describe the morphology of Type 1 Diabetes
insulitis: Leukocytic infiltrates (T lymphocytes)
describe the morphology of Type 2 Diabetes
Amyloid deposition within islets
describe the morphology of Type 2 Diabetes
Amyloid deposition within islets
what happens in Nondiabetic new borns of diabetic mothers:
increase in the number and size of islets as a response to maternal hyperglycemia
what are the 4 C/F of type 1 DM
polyruia, polydipsia, polyphagia and ketoacidosis
list how type 1 DM leads to polyuria and polydipsia
hyperglycemia → glycosuria → osmotic diuresis → polyuria → loss of water and electrolytes → along with hyperosmolarity due to hyperglycemia → deplete intracellular water → polydipsia
list how type 1 DM leads to polyphagia
def of insulin → catabolic metabolism → negative energy balance → polyphagia
list how type 1 DM leads to ketoacidosis
Severe insulin def with hyperglucagonemia → break down of adipose stores → increased FFAs → oxidized in the liver (glucagon) → ketone bodies → acetoacetic acid and B-hydroxybutyric acid → dehydration → ketoacidosis
what are the electrolyte disturbances in type 1 DM
- Lack of insulin shifts intracellular potassium to extracellular fluid
- Acidosis also shifts I.C K+ to E.C K+
- Osmotic diuresis also causes K+ and Na+ loss in urine
symptoms for DKA
: Shock, Abdominal pain / nausea / vomiting, Fruity odour ( exhaled ketones)
phyisical exam findings in DKA
altered mental status ( delirium / psychosis)
signs of dehydration (skin turgor, dry mucous membranes)
Lab findings in DKA
- Hyperglycemia, inc.H+ & dec. HCO3 – (Anion gap metabolic acidosis),
- inc. urine and blood ketone levels,
- leukocytosis.
- Normal/ inc. serum K+ , but depleted intracellular K+ due to transcellular shift from dec .insulin and acidosis.
- Osmotic diuresis K+ loss in urine total body inc. K+ depletion
inc .Na+ loss in urine total body Na+ depletion
lab findings in total body potassium depletion
- Normal/ inc. serum K+ , but depleted intracellular K+ due to transcellular shift from dec .insulin and acidosis.
- Osmotic diuresis K+ loss in urine total body inc. K+ depletion
inc .Na+ loss in urine total body Na+ depletion
determine Dx:
Marked insulin deficiency leads to ketonemia and ketonuria (acetoacetic acid & β-hydroxybutyric acid)
Seen most commonly in older patients with concurrent cardiac and renal pathology with stress / infection and increased insulin requirement
DKA
determine Dx:
Marked insulin deficiency leads to ketonemia and ketonuria (acetoacetic acid & β-hydroxybutyric acid)
Seen most commonly in older patients with concurrent cardiac and renal pathology with stress / infection and increased insulin requirement
DKA
Clinical features- Type II DM
- Patient >40 years
- Obese
- Polyuria, polydipsia, may present with weight loss
what is more common in type 2 DM than ketoacidosis
Hyperosmolar hyperosmotic syndrome (HHS) without ketosis is a more common
In contrast to type 1 diabetes, the frequency of ketoacidosis is______- in type II diabetes because
of higher ________- levels in these patients prevents unrestricted hepatic fatty acid oxidation and keeps the formation of ketone bodies in check.
lower , portal vein insulin
what are some symptoms in Type 2 DM
Thirst, polyuria, lethargy, focal neurologic deficits, seizures
[Type 2 DM]:
Sustained osmotic diuresis → Decompensated state (dehydration and increased S osmolality)
→ _______________ especially debilitated patient with inadequate water intake
Hyperosmolar nonketotic coma
Lab findings in HHS
Hyperglycemia (often > 600 mg/dL)
Increased serum osmolality (> 320 mOsm/kg)
Normal pH (no acidosis)
No ketones
Normal / inc. serum K+ , but depleted intracellular K+
Macrovascular disease:
- long-standing diabetes leads to accelerated atherosclerosis involving Aorta, large & medium sized muscular arteries
increased risk of myocardial infarction, stroke, and lower extremity gangrene.
Smaller vessels
more in HTN with DM
amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of the lumen
Hyaline arteriolosclerosis
describe morphology of Diabetic microangiopathy
diffuse thickening of the BM (capillaries of skin, skeletal muscle, retina, renal glomeruli,
and renal medulla)\
* nonvascular structures - renal tubules, bowman cap, peripheral nerves, placenta- thickened
by deposition of type IV collagen
* despite thickening , the capillaries are more leaky to plasma proteins
what are some Diabetic Ocular Complications in diabetic microangiopathy
retinopathy : hemorrhages, retinal exudates, microaneurysms, venous dilations, edema, and
thickening of the retinal capillaries (microangiopathy)
* cataract formation, glaucoma
what are some Diabetic neuropathy sx in diabetic microangiopathy
- peripheral, symmetric neuropathy of the lower extremities affecting both motor and sensory function
- Autonomic neuropathy: Disturbances in bowel and bladder function
neurologic changes - result of microangiopathy and *increased permeability *of the capillaries that supply the nerves, as well as direct axonal damage
- Formation of Advanced Glycation End Products: in DM
- nonenzymatic reactions between intracellular glucose-derived precursors (glyoxal, methylglyoxal, and 3-deoxyglucosone) and the amino groups of proteins.
AGEs bind to a specific receptor (______), which is expressed on inflammatory cells (macrophages & T cells, ______ and vascular smooth muscle.
RAGE, endothelium
5 Effects of AGE- RAGE signaling in vascular compartment:
- release of pro-inflammatory cytokines and growth factors from intimal macrophages
TGF β – deposition of basement membrane like material
VGEF – neovascularization – diabetic retinopathy - generation of reactive oxygen species in endothelial cells
- increased procoagulant activity on endothelial cells and macrophages
- enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix.
- AGEs can directly cross-link extracellular matrix proteins.
how do AGEs directly cross-link extracellular matrix proteins.
- Cross-linking traps plasma / interstitial proteins
- LDL trapped – accelerates atherosclerosis
- Albumin trapped – basement membrane thickening (microangiopathy)
Increased ______ from glycolytic intermediates causes PKC activation
DAG
what are 3 effects of Protein Kinase C activation
Proangiogenic
profibrogenic
vasoconstriction
Effects of Protein Kinase C activation : vasoconstriction
- Increase in vasoconstrictor endothelin and decreased vasodilator endothelial
nitric oxide synthase
Effects of Protein Kinase C activation :
profibrogenic
TGF β leads to deposition of extracellular matrix and BM
Effects of Protein Kinase C activation :
proangiogenic
VEGF implicated in the neovascularization characterizing diabetic retinopathy
Intracellular Hyperglycemia and Disturbances in Polyol Pathways.:
This excess glucose is metabolized by _________-to _______(Polyol) and then to ______ (Reaction that uses NADPH)
aldose reductase , sorbitol , fructose
NADPH is also required by the enzyme ________- for reducing [GSH]
glutathione reductase
unavailability of GSH - Increases cellular susceptibility to_______– ________
oxidative stress
insulin for glucose transport not required in what 4 areas
nerves, lenses, kidneys, blood vessels.
what is also known as (“glucose neurotoxicity by oxidative stress)”
diabetic neuropathy
determine DX:
is a slow-progressing form of autoimmune diabetes
* features of both Type 1 DM and Type 2 DM. Misdiagnosed as type II DM
* usually over age 30
Criteria
1. Age greater than 35 years
2. Positive autoantibodies to islet beta cells
3. Insulin independence for at least the initial 6 months after initial diagnosis
Latent autoimmune diabetes in adults (LADA) (DM 1.5)
what are the 8 important lab values in DM
-blood sugar estimation
- HbA1C
- serum insulin
-c-peptide
* Complete lipid profile -
* Blood urea and serum creatinine
* Microalbuminuria (albumin 50-300 mg/day)
* Urine albumin-to-creatinine ratio (UACR) >30 mg/g
describe HbA1C:
formed by nonenzymatic addition of glucose moieties to hemoglobin in red cells.
Unlike blood glucose levels, HbA1C is a measure of glycemic control over____ periods of time
long -periods of time = 2-3 months
HbA1C is relatively ______ by day-to-day variations.
unaffected
