Describe the pathophysiology of Type 1 Diabetes.
Cellular-mediated autoimmune destruction of pancreatic beta cells.
Which type of Diabetes is insulin dependent?
Type 1
In which type of diabetes is there little or no insulin secretion?
Type 1
What is the prevalence of idiopathic Type 1 Diabetes?
10%
What is the prevalence of immune mediated Type 1 Diabetes?
90%
What is the age of onset of Type 1 Diabetes?
75% of individuals develop it before age 30 but it is possible to acquire up to the tenth decade, peak onset is 11-13 yrs
Describe the pathophysiology of Type 2 Diabetes
Could be insulin resistant with insulin deficiency or a secretory defect with insulin resistance
With which type of Diabetes does obesity occur?
Type 2, usually abdominal obesity. Long-duration obesity is a common precipitating factor of diabetes!
What is the age of onset of Type 2 Diabetes?
Generally age 40 or older, but frequency is increasing in children
In which type of Diabetes is there a strong genetic predisposition?
Type 2
What comorbidities occur with Type 2 Diabetes?
HTN, dyslipidemia
Which group has the highest incidence of Type 2 Diabetes?
Black females and Native Americans
Which type of Diabetes presents islet cell antibodies (ICAs), antibodies to insulin, and autoantibodies to glutamic acid decarboxylase and tyrosine phosphatases?
85-90% of individuals with Type 1 Diabetes, when fasting hyperglycemia is detected
Describe the difference in Type 1 and Type 2 Diabetes with regard to insulin resistance.
Insulin resistance is unusual at diagnosis of Type 1 Diabetes but insulin resistance is usually caused by altered cellular metabolism leading to Type 2 Diabetes.
Describe the difference in Type 1 and Type 2 Diabetes with regard to insulin secretion.
Type 1 Diabetes results from a severe insulin deficiency or no insulin secretion at all, while at the time of diagnosis with Type 2 Diabetes, there is an increased production of insulin.
T/F Type 1 Diabetes is the most common pediatric chronic disease.
True, with a prevalence of 0.17% in US children.
What is Type 1 A Diabetes?
Autoimmune, more common.
What is Type 1 B Diabetes?
Non-immune, far less common than Type 1 A. It is secondary to other diseases like pancreatitis.
Which population has the highest prevalence of Type 1 B Diabetes?
People of Asian or African descent.
This genetic marker is strongly associated with Type 1A Diabetes and is associated with other diseases such as celiac, Graves, Hashimoto, and Addison diseases.
HLA-DQ and HLA-DR
Describe the process leading to autoimmune destruction of beta cells in Type 1A Diabetes.
The genetic marker along with environmental exposure to certain drugs, foods, and viruses result in the formation of autoantigens on the surface of pancreatic beta cells. Cellular immunity (T cytotoxic cells and macrophages) and humoral immunity (autoanti
At what point does hyperglycemia develop with the destruction of beta cells?
80-90% of insulin-secreting beta cells of the islet of Langerhans must be destroyed.
What is glucagon and how is it affected by insulin/diabetes?
Glucagon is a hormone produced by the alpha cells of the islet of Langerhans that acts in the liver to stimulate glycogenolysis and gluconeogenesis. Insulin normally suppresses glucagon production, so hypoinsulinemia leads to a marked increase in glucagon
What is amylin and how is it affected by insulin/diabetes?
Amylin is a beta-cell hormone which suppresses glucagon release. A decline in insulin will cause a decline in amylin secretion, leading to increased blood glucose.
What are the most common risk factors for Type 2 Diabetes?
Age, obesity, HTN, physical inactivity, and family history.
What is metabolic syndrome?
It is a constellation of disorders (central obesity, dyslipidemia, prehypertension, and an elevated fasting blood glucose level) that together confer a high risk of developing type 2 diabetes and associated cardiovascular complications.
Who does metabolic syndrome affect?
It develops during childhood and is highly prevalent among overweight children and adolescents, affecting approximately 55 million Americans.
What is the prevalence of insulin resistance in individuals with Type 2 Diabetes?
60-80%
How does obesity contribute to insulin resistance? (1/4)
Adipokines (leptin and adiponectin) are hormones produced in adipose tissue. Obesity results in increased serum levels of leptin and decreased levels of adiponectin. These changes are associated with inflammation and decreased insulin sensitivity.
How does obesity contribute to insulin resistance? (2/4)
Elevated levels of serum free fatty acids (FFAs) and intracellular deposits of triglycerides and cholesterol are also found in obese individuals. These changes interfere with intracellular insulin signaling and thus decrease tissue responses to insulin an
How does obesity contribute to insulin resistance? (3/4)
Inflammatory cytokines (tumor necrosis factor-alpha [TNF-?], interleukin-1-beta [IL-1?], and interleukin-6 [IL-6]) are released from intra-abdominal adipocytes or adipocyte-associated mononuclear cells; they induce insulin resistance and are cytotoxic to
How does obesity contribute to insulin resistance? (4/4)
Obesity is correlated with hyperinsulinemia and decreased insulin receptor density.
What is beta-cell exhaustion?
Beta-cell dysfunction (decrease in beta-cell mass and reduction in beta-cell function) develops and leads to a relative deficiency of insulin activity. A progressive decrease in the weight and number of beta cells occurs and many of the remaining cells de
What is ghrelin and how does it affect blood glucose?
It is a peptide produced in the stomach and pancreatic islets that stimulates growth hormone release. Decreased levels of circulating ghrelin have been associated with insulin resistance and increased fasting insulin levels.
What are incretins and how do they relate to blood glucose?
They are a class of peptides that are released from the GI tract in response to food intake and function to increase the sensitivity of beta cells to circulating glucose levels, thus improving insulin responsiveness to meals. Incretins also suppress gluca
What are the major acute complications of DM?
hypoglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic nonketotic syndrome
Which type of diabetes is more susceptible to hypoglycemia?
Type 1 Diabetes. They do not retain glucose counterregulatory mechanisms like those with Type 2 do. However, Type 2 diabetics who rely on exogenous insulin treatment may also be susceptible to hypoglycemia.
What are the symptoms of hypoglycemia?
pallor, tremor, anxiety, tachycardia, palpitations, diaphoresis, headache, dizziness, irritability, fatigue, poor judgment, confusion, visual disturbances, hunger, seizures, and coma
What is Diabetic Ketoacidosis (DKA)?
It is a serious complication related to a deficiency of insulin and an increase in the levels of insulin counterregulatory hormones (catecholamines, cortisol, glucagon, growth hormone). It is also known as Diabetic Coma Syndrome. The American Diabetes Ass
Who is more susceptible to DKA?
Individuals with Type 1 Diabetes because they are more insulin deficient.
How does insulin deficiency exacerbate DKA?
Insulin normally inhibits fat catabolism. With insulin deficiency, fat breakdown is enhanced and there is an increased delivery of fatty acids to the liver. This results in increased gluconeogenesis, hyperglycemia, and increased production of ketone bodie
What other factors exacerbate DKA?
Stressful situations such as infection, accident, trauma, emotional stress, omission of insulin, and medications that antagonize insulin.
What are the symptoms of DKA?
Kussmaul respirations (hyperventilation in an attempt to compensate for the acidosis), postural dizziness, central nervous system depression, lethargy, ketonuria, anorexia/weight loss, nausea, abdominal pain, thirst, dry mouth, polyuria, and a fruity or a
What is Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS)?
It an uncommon but significant complication of type 2 diabetes mellitus with a high overall mortality. It occurs more often in elderly individuals who have other comorbidities, including infections or cardiovascular or renal disease, and medications that
What are the clinical features and manifestations of HHNKS?
Less profound insulin deficiency, more profound fluid deficiency, a serum glucose level >600 mg/dl, a serum pH >7.30, a serum bicarbonate level >15 mg/dl, a serum osmolarity >320 mOsm/L, and either absent or small numbers of ketones in the urine and serum
What is the Somogyi effect?
It is a unique combination of hypoglycemia followed by rebound hyperglycemia. The rise in blood glucose concentration occurs because of counterregulatory hormones (epinephrine, GH, corticosteroids), which are stimulated by hypoglycemia. Excessive carbohyd
What is the dawn phenomenon?
It is an early morning rise in blood glucose concentration with no hypoglycemia during the night. It is related to nocturnal elevations of GH, which decrease metabolism of glucose by muscle and fat. Increased clearance of plasma insulin also may be involv
What are the microvascular chronic complications of DM?
retinopathies, nephropathies, and neuropathies
What are the macrovascular chronic complications of DM?
coronary artery, peripheral vascular, and cerebral vascular diseases
Why is strict control of blood glucose not recommended?
It is increases the 5 year mortality in high risk individuals. Several complex metabolic pathways are associated with persistent hyperglycemia and chronic complications including production of reactive oxygen species (oxidative stress).
What is the polyol pathway and how does it complicate DM?
Tissues that do not require insulin for glucose transport, such as kidney, red blood cells (RBCs), blood vessels, eye lens, and nerves, cannot down-regulate the cellular uptake of glucose; consequently, intracellular glucose is shunted into an alternate m
What is protein kinase C (PKC) and how does it complicate DM?
It is a family of intracellular signaling proteins that can become inappropriately activated in different tissues by hyperglycemia. Various consequences have been observed, including insulin resistance and production of proinflammatory cytokines; vascular
What is nonenzymatic glycation?
It is a normal process that involves the reversible attachment of glucose to proteins, lipids, and nucleic acids without the action of enzymes.
How does hyperglycemia affect nonenzymatic glycation?
Glucose becomes irreversibly bound to proteins in blood vessel walls, interstitial tissue, and cells, forming advanced glycation end products (AGEs). When AGEs attach to their receptor (RAGE) or act independently they have a number of properties that may
What are some conditions/complications that result from irreversible glycation? (1/5)
Trapping of proteins, including albumin, low-density lipoprotein (LDL), immunoglobulin, and complement, with thickening of the basement membrane or increased permeability in small blood vessels and nerves
What are some conditions/complications that result from irreversible glycation? (2/5)
Binding to cell receptors, such as macrophages, and inducing release of cytokines and growth factors that stimulate cellular proliferation in the glomeruli and smooth muscle of blood vessels
What are some conditions/complications that result from irreversible glycation? (3/5)
Induction of lipid oxidation, oxidative stress, and inflammation
What are some conditions/complications that result from irreversible glycation? (4/5)
Inactivation of nitric oxide with loss of vasodilation
What are some conditions/complications that result from irreversible glycation? (5/5)
Procoagulant changes on endothelial cells and promotion of platelet adhesion
What is the hexosamine pathway?
Like the polyol pathway, hyperglycemia leads to shunting of excess glucose into this pathway. This leads to O-linked glycosylation (attachment of groups of oligosaccharides directly to proteins) of several enzymes and proteins with alteration in signal tr
What is microvascular disease?
It is disease in capillaries which is a leading cause of blindness, end-stage kidney failure, and various neuropathies. Thickening of the capillary basement membrane, endothelial hyperplasia, thrombosis, and pericyte degeneration are characteristic of dia
What is diabetic retinopathy?
It is a chronic complication of microvascular disease and is the leading cause of blindness worldwide. It results from relative hypoxemia, damage to retinal blood vessels, and RBC aggregation. Those with retinopathy are more likely to develop glaucoma and
What is the age of onset of diabetic retinopathy?
It is the most common cause of blindness in adults younger than 60 years old.
Who is most susceptible to diabetic retinopathy?
Most individuals with diabetes will eventually develop this but it develops more quickly in those with Type 2 Diabetes, likely due to the long period of hyperglycemia before diagnosis.
What is the leading cause of decreased vision in those with diabetes?
Macular edema
What is diabetic nephropathy?
The glomeruli are injured by protein denaturation from high glucose levels, by hyperglycemia with high renal blood flow (hyperfiltration), and by intraglomerular hypertension exacerbated by systemic hypertension. Progressive changes include glomerular enl
What is the first sign of kidney dysfunction?
Microalbuminuria/proteinuria (protein in the urine). Continuous proteinuria generally heralds a life expectancy of less than 10 years. Death from kidney failure is much more common in individuals with type 1 diabetes mellitus than in those with type 2 dia
What is diabetic neuropathy?
It is the most common cause of neuropathy in the Western world and is the most common complication of diabetes. The underlying pathologic mechanism includes both metabolic and vascular factors related to chronic hyperglycemia with ischemia and demyelinati
What are some complications caused by neuropathy?
diabetic neuropathic cachexia, and visceral manifestations associated with autonomic neuropathy (e.g., delayed gastric emptying, diabetic diarrhea, altered bladder function, impotence, orthostatic hypotension, and heart rate variability). Chronic hypergly
What is macrovascular disease?
lesions in large- and medium-sized arteries, which increases risk for accelerated atherosclerosis and coronary artery disease, stroke, and peripheral vascular disease. Unlike microangiopathy, atherosclerotic disease is unrelated to the severity of diabete
Who is more susceptible to macrovascular disease?
Those with Type 2 Diabetes.
What is coronary artery disease?
It is the most common cause of morbidity and mortality in individuals with diabetes mellitus. Mechanisms of disease include hyperglycemia and insulin resistance, high levels of low-density lipoproteins (LDLs) and triglycerides, low levels of high-density
What is the relation between stroke and diabetes?
Stroke is twice as common in those with diabetes (particularly type 2 diabetes) as in the nondiabetic population. Hypertension, hyperglycemia, hyperlipidemia, and thrombosis are definite risk factors.
How does Peripheral Vascular Disease (PVD) affect those with diabetes?
The increased incidence of peripheral vascular disease (PVD), with claudication, ulcers, gangrene, and amputation, in the individual with diabetes has been well documented. Peripheral vascular disease in those with diabetes is more diffuse and often invol
How does PVD progress in those with diabetes?
Occlusions of the small arteries and arterioles cause most of the gangrenous changes of the lower extremities and occur in patchy areas of the feet and toes. The lesions begin as ulcers and progress to osteomyelitis or gangrene requiring amputation. Loss
What complications of diabetes increase these individuals' risk for infection?
1) impaired senses reduces protection from injury and increases risk for repeated injury 2) hypoxia, due to glycosylated RBCs, reduces delivery of oxygen and impairs healing 3) pathogens proliferate due to increased glucose in the body 4) blood supply is