184/185. Diabetes Flashcards
ROS generation results in DNA strand breaks with activation of __
__ activation results in inactivation of GAPDH
- furthers ROS production by mitochondria and shunting of glucose and glycolytic intermediates into pathways mediating diabetic complications (polyol, PKC, AGE, glucosamine)
PARP (ADP ribose polymerase)
Not absolutely dependent upon exogenous insulin
Not prone to ketoacidosis
Often obese
Historically was typically diagnosed after the age of 40 yo
- recognized with increasing frequency in children d/t childhood obesity
Strong family history
Type 2 DM
__ will decrease w/ time as islet cells are destroyed due to lack of antigen
Islet cell antibodies
Vast majority of genes associated with Type 2 DM affect __ function
- as opposed to insulin resistance
Leads to glucotoxicity, lipotoxicity, ER stress, mitochondrial dysfunction, oxidative stress, islet inflammation, increase islet amyloid polypeptides
Beta-cell
Microvascular complication of diabetes that is the leading cause of adult renal failure
Nephropathy
Autoantibodies to the zinc transporter which transports zinc into insulin granules (expressed in beta cells)
Present in 60-80% at diagnosis of type 1 DM
ZnT8 autoantibodies
What is the key electrolyte to focus on when treating diabetic ketoacidosis?
Will need to add __ supplements to fluid when it enters normal range
K+
Hyperglycemia-induced complication
Increased intracellular glucose results in increase __ formation and protein glycation
- __s damage target cells by 3 mechanisms:
1. function of __-modified proteins may be altered
2. components of the ECM modified by __s may interact abnormally with other matrix components and/or integrins
3. plasma proteins modified by __ precursors are able to bind to a receptor for __s which results in the generation of ROS
There is an increase of their receptors
AGE
Patients with Type 1 diabetes who are treated with insulin are at a higher risk of __ than type 2 diabetics
Hypoglycemia
Acute effect of insulin deficiency:
- In absence of insulin proteolysis and breakdown of __ occur
- __ output increases secondary to glucogenolysis and gluconeogenesis
- __ are metabolized into ketoacids which decreases plasma pH
- __ occurs secondary increased hepatic glucose and decreased peripheral uptake of glucose
- Hyperglycemia causes __ with resulting dehydration and loss of electrolytes in urine
- TGs
- Hepatic
- Free fatty acids
- Hyperglycemia
- Glucosuria
Complex metabolic disorder
- multiple factors contribute
Defined as decreased ability of insulin to lower circulating glucose concentrations
- impaired stimulation of glucose utilization by muscle and fat
- impaired suppression of glucose production by liver
Insulin resistance
Fasting plasma glucose more than 100 but less than 125
Impaired fasting glucose
3 most common microvascular complications to worry about in diabetic patients
Retinopathy
Nephropathy
Neuropathy
The combination product of hemoglobin A and glucose (glycation)
Reflects the average levels of glucose in the blood for the previous several months and therefore indicates the degree of diabetic control
HgbA1c
Leading cause of death among pts with diabetes
Ischemic heart disease
Symptoms of type 1 diabetes?
Due to glucose spilling into urine and water following
Due to not incorporating calories into tissues
Polyuria (95%)
Weight loss (60%)
Fatigue (50%)
Diabetes is a chronic metabolic disorder that impacts the metabolism of what 3 types of energy sources?
Carbohydrates
Protein
Fat
What kind of immune cells are thought to be causative of Type 1 DM?
T-cells
What are the peak ages for Type 1 DM diagnosis?
10-14yo
Hyperglycemia-induced complication
High glucose flux through constitutive glucose transporters on the surface of endothelial cells increases intracellular glucose levels and results in the generation of __ by mitochondria
ROS
Autoantibodies that are present in 40-50% at diagnosis
Presence of this with ICA are highly predictive of diabetes
IAA (Insulin autoantibodies)
2 hour plasma glucose more than 140 but less than 200
Impaired glucose tolerance
Microvascular complication of diabetes that is the leading cause of nontraumatic amputations in adults
Presents in a stocking-glove distribution
Can lead to diabetic ulcers
Neuropathy
Hyperglycemia-induced complication
Activation of ___
- intracellular hyperglycemia results in increased DAG synthesis with subsequent activation of __
- increased __ activity has a variety of effects in endothelial and other cell types
Increase __ leads to increase collagen, fibronectin, decrease fibrinolysis, and increased ROS
Protein Kinase C
What kind of obesity has a major impact on underlying insulin sensitivity
Central obesity
Aspect of lifestyle changes for Type 2 DM pts:
- decrease fat content and total calories
- decreased saturated fat
- decrease salt for hypertension
- healthy diet
- weight reduction in obese patients
Used along with moderate-intensity exercise and smoking cessation
Nutrition therapy
Type 1 diabetes is associated with certain __ types
In particular, DR3 and/or DR4
Some of these genes are unique to Type 1 DM and some also associated with other autoimmune disorders
HLA
Occurs due to autoimmune destruction of beta cells in pancreatic islets
Insulitis can be seen on histology during the development of this disease
Type 1 diabetes
Highly associated with insulin resistance
Obesity
What is the mechanism for hyperkalemia occurring diabetic ketoacidosis?
Increased H+/K+ transporter therapy moving H+ into cells and K+ into ECF
Accounts for 5-10% of diabetes worldwide
Insulinopenic
- dependent on exogenous insulin for life
- ketosis prone under basal conditions
Type 1 diabetes
Absence of __ phase insulin release is common in type 2 DM
This causes hyperglycemia to ensue
first
Antibodies that are present in 70-80% at diagnosis of type 1 DM
Persist longer than ICA
GADA (glutamic acid decarboxylase autoantibodies)
Fasting plasma glucose < 100
2 hour plasma glucose < 140
Normal
Fasting plasma glucose more than 125 and 2 hour plasma glucose more than 200
Diabetes
HLA locus demonstrates strong associated with type 1 DM
There is a significant effect of insulin and __ genes as well
PTPN22
Markers of autoimmunity useful for predicting disease and diagnosing disease when presentation is not classic for type 1 DM
Islet cell antibodies
Antibodies to the transmembrane protein tyrosine phosphatase
Present in about 60% of individuals at diagnosis
IA2A (Insulinoma associated 2 autoantibodies)
Hyperglycemia with a secondary decrease in plasma pH due to increased production of ketoacids is referred to as
Diabetic ketoacidosis
Adipose tissue inflammation is due to __ which interfere with insulin signaling
- along with lipid metabolites
Cytokines
Islet cell antibodies present years to months before onset of clinical type 1 DM
Those with __ or more autoantibodies are at highest risk for progressing to type 1 diabetes
2
Obesity =>
- skeletal muscle: increased FFA uptake, increased extramyocellular adipose, macrophage activation/recruitment, ER stress
- Adipose: Adipocyte hypertrophy, macrophage recruitment, macrophage polarity switch, increased cytokine production, increased lipolysis, ER stress
- Liver: increased lipid content, steatosis, kupffer cell activation/recruitment, increased cytokine production, ER stress
Thus, obesity leads to insulin resistance and __
Inflammation
People with type 2 DM don’t increase insulin secretion in response to hyperglycemia due to decrease __
- central obesity has a major impact
Decreased beta-cell compensation for the insulin resistance
Insulin sensitivity
Detected by incubating patient serum with pancreatic sections
75-80% of caucasian children are positive for this antibody at the time of type 1 DM diagnsosis
ICA (islet cell autoantibodies)
Hyperglycemia-induced complication
Increased flux of glucose and other sugars through the polyol pathway
- hyperglycemia is associated with increased intracellular glucose in insulin-unresponsive tissues which results in the conversion of glucose to the polyol __ by aldose reductase
- this reaction consumes NADPH which is required for regenerating reduced glutathione
- as reduced glutathione is depleted oxidative stress is induced or exacerbated
Sorbitol
Diabetic ketoacidosis treatment includes 2 separate treatments
- IV insulin therapy
2. IV saline (.9 first then alternating .9 and .45 after fluids are restored)
Microvascular complication of diabetes that is the leading cause of adult blindness
Retinopathy
__ is exacerbated by obesity, sedentary lifestyle, age, and some medications (steroids)
Insulin resistance
