What is insulin?
-Anabolic hormone released from pancreas required for the
uptake of glucose by liver, muscle, and adipose tissue
-Acts as a key to open up receptors for glucose, not dependent on levels in blood
-
Brain, RBCs, kidneys, and lens of eyes
do NOT require insu
What is the endocrine and exocrine function of the pancreas?
Releases insulin and glucagon
Releases digestive enzymes and alkaline fluids
What are the islets of Langerhans?
-Alpha cells: secrete glucagon
-Beta cells: secrete insulin and amylin
-Delta cells: secrete somatostatin and gastrin
-F/PP cells: secrete pancreatic polypeptide
What is glucagon?
-Hormone antagonist to insulin that increase blood glucose levels
-Negative feedback and released with low blood glucose levels
-Stimulates glycogenolysis in liver (breakdown of glycogen into glucose) and glyconeogenesis (creation of new glucose)
-Stimula
How does insulin function?
-Promoted by increased blood glucose levels
-Facilitates rate of glucose uptake into body cells
-Sensitivity of insulin receptor is key to maintaining normal cellular function, not insulin resistance
-GLUT 4 helps with glucose diffusion into cell
What is amylin?
-Peptide hormone secreted in response to nutrient stimuli, along with insulin
-Allows for satiety effect to suppress appetite
-Regulates blood glucose by delaying nutrient uptake and suppressing glucagon secretion after meals
-Antihyperglycemic effect (pr
What is pancreatic somatostatin?
-Essential in carbohydrate, fat, and protein metabolism
-Regulatory hormone that inhibits alpha and beta cell function
What is gastrin?
Thought to control the secretion of glucagon
What are the names of the cells with exocrine fnction?
acinar and duct cells
What is pancreatic polypeptide?
-Released by F cells in response to hypoglycemia and protein-rich meals
-Promotes gastric secretion to break down food into glucose
When does insulin increase?
Increase in:
-blood glucose
-amino acids
-potassium
-phosphate
-magnesium
-glucagon
-gastrin
When does insulin decrease?
-Low blood glucose
-High insulin levels
-Stimulation of alpha cells
What is the cycle of hormones when we eat a meal?
-Eating increases blood glucose levels to slightly higher than homeostasis
-Pancreas release insulin to signal liver to take up excess glucose and store it as glycogen
-Glucose levels drop, and we eventually fall below our homeostatic set point
-Pancreas
The global prevalence of diabetes has __________.
increased (and will continue to increase)
What is diabetes mellitus?
Inability to regulate glucose, leading to inadequate metabolism of macronutrients
What is the pathophysiology of Type 1 diabetes mellitus?
-Absolute or significant deficit of insulin
-Autoimmune and cell-mediated immunodestruction of beta cells in pancreas
-Multifactorial (genetic, environmental)
-10% of those with DM have Type 1
-Can cause
hyperglycemia, hyperketonemia, and ketoacidosis
What is autoimmune type 1 diabetes mellitus?
-Type 1A pancreatic atrophy and cell-mediated destruction of pancreatic beta cells due to recognition as non-self
-Autoantibodies created and T-cell/macrophages attack beta cells
-Loss of insulin production and relative excess of glucagon occurs
What is nonimmune type 1 diabetes mellitus?
-Occurs secondary to other diseases (pancreatic)
-Can be due to idiopathic diabetes (type 1B), where cause is unknown
What is the genetic susceptibility of type 1 DM?
-10-13% have first-degree relative with type 1 DM
-Identical twins have 50% chance if one develops type 1 DM
-Strong association and increase of chances with large amounts of MHC II
What environmental factors cause type 1 DM?
-Occurs in children after viral infection or due to H. pylori
-Exposure to cow's milk proteins
-Relative lack of vitamin D
How does type 1 DM work?
-Genetic predisposition and environmental factors cause autoantigens to form on beta-cells
-APCs present autoantigens and helper T lymphocytes are activated
-Macrophages, CD8 cells, and
antiGAD65 antibodies destroy beta cells
What is insulinitis?
-Lymphocytes and macrophages infiltrate and destroy beta cells
-Autoantibodies are produced against islet cells, insulin, glutamic acid decarboxylase (GAD), and other proteins
What cells are attacked in type 1 DM?
-Alpha and beta cells, reducing insulin, amylin, and causing excess of glucagon (in response to lack of insulin)
-Hyperglycemia occurs with excess glucagon signaling liver to release glycogen/glucose
What are the S&S of hyperglycemia?
Dry mouth
Increased thirst
Blurred vision
Weakness/headache
Frequent urination
What causes polyphagia?
Insulin deficiency means decreased glucose uptake, causing protein breakdown, which leads to weight loss, then hunger
What causes polydipsia?
Insulin deficiency causes excess glycogen, which leads to more glucose production and thus hyperglycemia, which causes body to release glucose and other electrolytes, causing thirst, but imbalance will cause circulatory failure eventually
What causes hyperketonemia?
Insulin deficiency causes lipolysis, which creates ketones in excess, which can lead to CNS depression and coma
What are the clinical manifestations of type 1 DM?
-Polydipsia
-Polyuria
-Polyphagia
-Nocturia that is high in glucose
-Fatigue, lethargy from lack of energy
-Weight loss and blurred vision from breakdown of proteins and fats for nutrients
What is the diagnostic criteria for type 1 DM?
-Presence of clinical manifestation
-Fasting blood glucose of >126 mg/dL and random of >200 mg/dL
-Urinalysis for ketones and glucose (which should never be in urine)
-Glycosylated hemoglobin (HbA1c) that is >8%
What is glycosylated hemoglobin levels?
-Permanent attachment of glucose to hemoglobin molecules
-Look at average glucose exposure over RBC life (120 days)
ex. 8% - 183 mg/dL on average for 3 months
What is the glucose tolerance test?
-Given 50-100 mg of glucose dissolved in water
-Blood sugar tested 1 hour, 2 hours, and 3 hours after ingestion
-Diagnostic >190 after hour and >165 after 2 hours
What is the treatment for type 1 DM?
-Glycemic control to keep glucose between 70-120 mg/dL via self-monitoring blood glucose systems or tracking carb/nutrient intake
-Increase exercise
-Insulin replacement therapy (rapid onset/short acting/regular; intermediate acting, slow onset/long actin
When is rapid-acting insulin administered?
Immediately before a meal
When is short-acting and intermediate-acting insulin administered?
Throughout the day
When is long acting insulin administered?
Nighttime
When is insulin checked and where is it administered?
Checked before and after meals, and administered into subcutaneous tissue
What are insulin pens?
Adjustable and reusable insulin giver
What is an insulin pump?
Pads attached to subcutaneous tissue and uses continuous glucose sensor that connects with monitor to check glucose levels (artificial pancreas)
What is the pathophysiology of type 2 DM?
-Insulin resistance due to reduced tissue sensitivity (cannot bind)
-Causes reduction in adequate insulin secretion
What are the risk factors of type 2 DM?
-
Obesity
in 60-80% of those with DM
-Age greater than 30, but decreasing as population under 25 is becoming more obese (MODY)
-Family history
-Native American, Hispanic, African American
What is metabolic syndrome?
-Cluster of different types of conditions that increase the risk of heart disease, stroke, and type 2 DM
-Prevalence in African, Asian, Pacific islander, Native American, Latino ancestry
-Affects 40% of age of 60 years
-Combines 3 of issues:
*abdominal ob
What are the risk factors for metabolic syndrome?
-Central obesity
-Dyslipidemia
-Pre-hypertension
-Elevated resting blood glucose level
How does type 2 DM work?
-Environmental factors cause insulin resistance
-Genetic factors cause impaired insulin release
-Muscles have decrease glucose uptake and there is an increased hepatic glucose output
-Hyperglycemia occurs
What occurs with insulin resistance?
-Increased production of adipokines (pro-inflammatory cytokines released by adipose tissue) that causes high leptin resistance
-Elevated serum free fatty acids and intracellular lipid deposits
-Reduced insulin-stimulated mitochondrial activity in
liver, m
What is beta cell dysfunction?
-Beta cell mass is decreased (possible genetic cause but NOT autoimmune related)
-Inflammation and changes in adipokines
What are the changes of glucagon in type 2 DM?
-Pancreatic alpha cells are less responsive to glucose inhibition, which causes hyperglycemia
-High levels of glucagon increase hepatic production of glucose
What are the demands of the body due to type 2 DM?
-Decreased activity of ghrelin, which leads to insulin resistance, which increase demand for insulin synthesis
-Hyperinsulinemia occurs with tissue effects from insulin
-Increased glucagon in response to excess insulin
What are the clinical manifestations of type 2 DM?
-Often asymptomatic, which takes a toll on the body
-Manifestations are vague, but can be similar to type 1 DM
-Visual changes
-Change in kidney function
-CAD, PVD
-Recurrent infections
-Neuropathy
What is the diagnostic criteria of type 2 DM?
-Presence of clinical manifestations
-Fasting >126 mg/dL; pre 110-125; random >200 mg/dL
-Distinguish between autoimmune response by looking for antigens in pancreas
-Test for presence of long-term complications
What is the treatment of type 2 DM?
-
Weight control via diet and exercise
, which can reverse type 2 DM
-Oral glycemic agents
-Insulin replacement therapy
-Goal is to maintain optimal blood glucose levels
Why do people with type 2 DM not receive insulin?
They are producing insulin, but their body is not using it - need to control excess glucose produced
What is the pathophysiology of gestational diabetes?
-Glucose intolerance with onset of pregnancy (15% of pregnancies)
-Usually temporary but can lead to type 2 if genetic propensity
-Requires diet modifications, exercise, and possibly insulin due to metabolic demands of host and fetus
What occurs if gestational diabetes is left untreated?
-Fetal macrosomia (large fetuses, 9-12 pounds) due to excess blood glucose that needs excess insulin
-Hypoglycemia (excess insulin once placenta cut and glucose levels dropped) and hypocalcemia of fetus
-Birth defects
What are the acute complications of diabetes?
Related to hypoglycemia
-Excessive insulin dose
-Inadequate food intake or vomiting
-Strenuous exercise or infection increase metabolic needs
Diabetic ketoacidosis
Hyperglycemia hyperosmolar nontetotic syndrome (HHNK)
Somogyi effect
Dawn phenomenon
What are the clinical manifestations of hypoglycemia?
-Tachycardia, palpitations
-Diaphoresis
-Tremors
-Pallor
-Arousal anxiety
What is the treatment of hypoglycemia?
-Glucose tablets (15-20 g) for conscious individuals
-Glucagon can be given by EMS, hospital for emergency use
What is diabetic ketoacidosis?
-Absolute or relative deficiency of insulin and increase in insulin counterregulatory hormones
-
Most common in type 1 DM
, rarely in type 2 DM
-Precipitating factors: illness trauma, surgery, MI
-Causes increased fat mobilization with release of fatty ac
What are the clinical manifestations of DKA?
-Polyuria and dehydration
-Kussmaul respirations (fast, deep breathing to offset acidosis)
-Sweet or fruity breath odor due to release of acids
-Serum glucose >250
-Serum pH <7.30 and presence of anion gap
-Presence of urine ketones
-Total body potassium
What is the treatment of DKA?
-Administration of insulin to decrease glucose levels
-Slow fluid and electrolyte replacement
What is HHNS?
-Life-threatening emergency precipitated by infections, meds, non-adherence to diabetes treatment, coexist disease
-Associated with
type 2 DM
-Very dehydrated
-Insulin deficiency and elevated glucose (over 1000)
What are the clinical manifestations of HHNS?
-Glycouria, polyuria
-Dehydration, coma
-Glucose >600 mg/dL
-Absent or low urine ketones
What is the treatment of HHNS?
-Insulin infusion combined with fluid replacement
-Electrolyte replacement
What is the Somogyi effect?
-Hypoglycemia with rebound hyperglycemia caused but counterregulatory hormones that cause gluconeogenesis
-Most common in type 1 DM and in children
What is the dawn phenomenon?
-Early morning glucose elevation without nocturnal hypoglycemia
-Related to nocturnal GH elevation, which decreases metabolism of glucose by muscles and fat, leaving it elevated in blood
How is the dawn phenomenon treated?
Alter timing and dose of nighttime insulin
What are the chronic complications of diabetes?
-Microvascular (retinopathy, nephropathy)
-Macrovascular (coronary, cerebrovascular, peripheral arteries)
-Neuropathy (nerve degeneration)
-Infection
direct results of hyperglycemia
What is microvascular disease?
-Thickening of capillary basement membrane, endothelial cell hyperplasia, thrombosis, pericyte degeneration
-Hyperglycemia must be present for this to occur
-Causes hypoxia and ischemia to target organ
What is diabetic retinopathy?
-Leading cause of blindness worldwide
-Develops more rapidly in type 2 DM
-Causes maculopathy (progressive process that accompanies retinal capillary permeability, vessel occlusion, and ischemia)
-Macular edema (fluid accumulation of sorbitol and retinal
How is diabetic retinopathy treated?
-Laser treatment
-Vitrectomy
-Intravitriol steroids
-Vascular and endothelial growth factors
-Renin-angiotensin system inhibitors
What is diabetic nephropathy?
-Most common cause of end-stage kidney disease in western world
-Cause glomerular enlargement
-Glomerular basement thickening
-Microalbuminuria
How is diabetic nephropathy treated?
-Tight glucose control and ACE inhibitors/angiotensin II receptors blockers
-Aggressively treated HTN
*hyperglycemia damages nephrons and they must be protected
What is diabetic neuropathy?
-Most common complication of diabetes
-Sensory deficit that precedes motor deficit in extremities
-"Dying back" neuropathy where distal portions of neurons are progressively affected, resulting in axonal and Schwann cell degeneration
-Distal symmetrical p
What sensations do small and large nerve fibers regulate?
-Small: neuropathic pain; will lead to loss of sensation
-Large: proprioception, so cannot locate pain on body (usually on hands and feet) or notice infection, injury
What is macrovascular disease?
-Lesions in large and medium-sized arteries from excess glucose (hyperglycemia)
-Advanced glycation end-products (AGE) attach their receptor (RAGE) to walls of blood vessels
-Promotes oxidative stress, inflammation, endothelial and vascular smooth muscle
What is CAD?
-Most common cause of morbidity and mortality (up to 75%) for all with diabetes
-Increase with duration, not intensity, of diabetes
-Consequence of accelerated atherosclerosis, HTN, increased risk for thrombus formation
-Can result in MI; cardiomyopathy h
What is a stroke?
-Twice as common in those with diabetes, esp type 2 DM
-Survival rate is small for those with diabetes
-Consequence of accelerated atherosclerosis, HTN, increased risk for thrombus
-Treated via management of BP, hyperglycemia, lipidemia
What is peripheral arterial disease?
-Increase for those esp with type 2, PAD, neuropathy, gangrene, amputation
-Atherosclerosis combined with peripheral neuropathy causes foot lesions that lead to 60% of non-traumatic amputations in US
-Referral to specialists can reduce amputation rates by
How does infection affect diabetes?
Mortality and morbidity increase with risk due to:
-Impaired sense, hypoxia
-Rapid pathogenic replication due to increased glucose
-Decreased blood supply
-Suppressed immune system
-Delayed wound healing