Pathophysiology Chapter 041

Elsevier items and derived items © 2010, 2005 by Saunders, an imprint of Elsevier Inc.

CHAPTER 41DIABETES MELLITUS


REGULATION OF GLUCOSE METABOLISM

Hormonal Regulation• Insulin is synthesized in the pancreas by the β

cells of the islets of Langerhans• β cells produce proinsulin• α cells produce glucagon• δ cells produce somatostatin• F cells produce pancreatic polypeptide


REGULATION OF GLUCOSE METABOLISM (CONT.)

Hormonal Regulation• Ingestion of nutrients stimulates the release of

glucose–dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) from cells in the gut; these stimulate the production of insulin and inhibit glucagon

• Insulin stimulates diffusion of glucose into adipose and muscle tissue

• Glucose oxidized in the cell (glycolysis) and used primarily for glycogenesis



Hormonal Regulation• In the fasting state, glucose is produced by

glycogenolysis and gluconeogenesis while insulin secretion falls to basal level

• Glucagon is responsible for most glucose production in fasting state

• Other counterregulatory hormones (corticosteroids, growth hormone, catecholamines) augment glucose production



Exercise• Initially insulin levels drop and glucagon and

catecholamine levels rise, increasing production of free fatty acids (FFAs) and stimulating glycogenolysis

• Rise in glucose to meet energy demands• Muscle tissue increases metabolism of glucose as

exercise continues, increasing insulin sensitivity and maintaining normal blood glucose levels in the presence of lower insulin levels



Stress• Production of stress hormones (corticosteroids

and catecholamines) increase production of glucose in the liver and glucagon in the pancreas, and decrease the utilization of glucose

• Catecholamines increase production of FFAs and inhibits glucose uptake in the periphery

• All of these events lead to hyperglycemia


GLUCOSE INTOLERANCE DISORDERS

Classification of Glucose Intolerance Disorders• Type 1 diabetes mellitus• Type 2 diabetes mellitus• Other specific types of diabetes mellitus• Gestational diabetes mellitus


GLUCOSE INTOLERANCE DISORDERS (CONT.)

Type 1 Diabetes Mellitus • Characterized by destruction of the β cells of the

pancreas• Usually diagnosed between 5 and 20 years of age• Etiology may be immune-mediated or idiopathic

(without autoimmune markers or HLA association)



Type 1 Diabetes Mellitus• Results in absolute insulin deficiency• Overproduction of glucagon stimulates

glycogenolysis and gluconeogenesis• Glucose levels rise, leading to polyuria,

polydipsia, and polyphagia• FFAs are transformed into ketones, leading to

ketoacidosis







Type 2 Diabetes Mellitus• Most common form of DM• Non-Caucasian and elderly are disproportionately

affected• Common risk factors include obesity, aging, and

sedentary lifestyle• Insulin resistance and β cell dysfunction lead to a

relative lack of insulin





Type 2 Diabetes Mellitus• Polyuria, polydipsia, and polyphagia may be more

subtle• Ketoacidosis is uncommon• Hyperglycemic hyperosmolar nonketotic (HHNK)

coma can develop due to severe dehydration, more common in older adults





Other Specific Types of Diabetes• Genetic defects of β cells—mature onset of

diabetes of the young (MODY)• Genetic defects in insulin action• Disease of the exocrine pancreas• Endocrinopathies• Drug/chemical/infection-induced diabetes



Gestational Diabetes Mellitus• Disorder of glucose intolerance of variable

severity with onset during pregnancy• Closely resembles type 2 DM• Most likely precipitated by the presence of

placental hormones• Management through dietary counseling,

exercise, and blood glucose/ketone monitoring





Pre-Diabetes• Impaired glucose tolerance and impaired fasting

glucose tolerance• Intermediate stages between normal glucose

metabolism and diabetes• Represent risk factors for the development of

diabetes and onset of cardiovascular disease





Screening for Diabetes• All adults older than age 45 at least every 3 years• Individuals with risk factors should be screened

earlier or more frequently


CLINICAL MANIFESTATIONS AND COMPLICATIONS

Acute Hyperglycemia• Commonly caused by alterations in nutrition,

inactivity, or inadequate use of antidiabetic medications

• Symptoms: polyuria, polydipsia, polyphagia, nausea, fatigue, blurred vision

• More prone to infections


CLINICAL MANIFESTATIONS AND COMPLICATIONS (CONT.)

Chronic Hyperglycemia• May lead to systemic changes over time and

increase the risk of other diseases, including metabolic syndrome, hypertension, cardiovascular disease, and stroke

• Complications are categorized as vascular and neuropathic



Vascular Complications• Macrovascular: damage to large blood vessels;

leads to CVD and stroke• Microvascular: retinopathy and nephropathy from

abnormal thickening of the basement membrane in capillaries; may lead to blindness and renal failure



Macrovascular Complications• DM is an independent risk factor for coronary

artery disease (CAD)• CAD risk factors, such as dyslipidemia,

hypertension, and impaired fibrinolysis are present in uncontrolled DM and can improve with blood glucose control



Microvascular Complications• Hyperglycemia disrupts platelet function and

growth of the basement membrane• Thickening of basement membrane may improve

with glycemic control• Risk factors of microvascular complications

include hypertension and smoking



Neuropathic Complications• Diabetic neuropathy

• Autonomic dysfunction: GI disturbances, bladder dysfunction, tachycardia, postural hypotension, and sexual dysfunction

• Sensory disturbances include carpal tunnel syndrome, paresthesias, or dysesthesias in extremities



Neuropathic Complications• Excessive glucose is thought to interfere with

myoinositol in neurons and reduced myoinositol in peripheral nerves

• Glycemic control may prevent or improve symptoms of diabetic neuropathy



Complications in Pregnancy• Type 1 DM: higher risk of perinatal infant

mortality and congenital abnormalities• Glycemic control before conception and during

pregnancy may reduce these risks


TREATMENT AND EDUCATION

Nutrition• Cornerstone of diabetes therapy• May involve changing the composition of the diet,

meal patterns and timing, and caloric consumption

• Attention to energy consumption and energy expenditure


TREATMENT AND EDUCATION (CONT.)



Protein• Used in the repair and growth of tissue• 4 calories/g• Stimulates the secretion of insulin without

increasing plasma blood glucose• Recommended daily allowance 0.8 g protein/kg of

body weight• Excessive protein may cause nephropathy



Fat• Saturated, monounsaturated, and unsaturated• 9 calories/g• Dietary saturated fat and cholesterol may lead to

hypercholesterolemia• Hypertriglyceridemia increases risk of CAD and

diabetes • Recommendations include limiting saturated fat

to less than 7% of total intake and <200 mg of cholesterol daily



Carbohydrates• Categorized as monosaccharides and

polysaccharides• 4 calories/g• Carbohydrate intake can be monitored with

carbohydrate counting• Glycemic load and index may also be of benefit



Alcohol• 7 calories/g• Intake of alcohol should be limited to 1 drink per

day for women, 2 per day for men and avoided in the presence of poor glycemic control, pancreatic/liver/renal disease, severe triglyceridemia, advanced neuropathy, pregnancy, or alcoholism



Obesity and Eating Disorders• Strongest risk factor for DM• Obesity: a body mass index (BMI) >30 kg/m2

• Recommendations include a nutritionally complete diet, program of maintenance, and exercise

• Bulimia and anorexia may be more common in type 1 DM; careful assessment is warranted



Exercise• Recommended for all types of DM• Lowers cardiovascular risk factors• May be beneficial toward weight reduction or

maintenance• May lower medication requirements • Type 1 DM at risk of hypoglycemia and

ketoacidosis



Oral Antidiabetic Agents• Sulfonylureas: induce insulin release by β cells,

augment the action of insulin in glucose disposal, diminish insulin clearance by liver, and reduce hepatic glucose production

• Biguanides: suppress hepatic gluconeogenesis and enhance glucose uptake by peripheral tissues



Oral Antidiabetic Agents• α-Glucosidase inhibitors: diminish postprandial

hyperglycemia by delaying carbohydrate absorption

• Thiazolidinediones: increase tissue sensitivity to insulin and inhibit hepatic gluconeogenesis





Incretins and Amylins• Incretins: inhibit enzymatic breakdown of the

incretin hormones, GLP-1, and GIP• Amylins: amylin-mimetic agents used in

conjunction with insulin for the management of glycemia



Insulin• Required for all patients with type 1 DM and

approximately 35% of those with type 2 DM• Provides replacement of the deficient hormone• Different types: rapid-acting, short-acting,

intermediate-acting, and long-acting





Hypoglycemia• Most common complication of insulin therapy• Symptoms include pallor, tremor, diaphoresis,

palpitations, and anxiety• Education on symptoms and management of

hypoglycemia should be addressed with all diabetic patients



Other Complications of Insulin Therapy• Lipoatrophy: hollows in skin surface caused

by the destruction of subcutaneous adipose tissue

• Lipohypertrophy: increase in subcutaneous tissue because of insulin-stimulated growth of adipose tissue at injection sites

• Insulin edema: generalized accumulation of fluid

• Insulin resistance: exacerbated by obesity



Stress Management• Management of DM can be stressful• Patients with DM at higher risk of depression• Plays an important role in improving quality of life

and reducing impact of stress on glycemic control



Assessment of Efficacy• Glycosylated hemoglobin is used to determine

long-term glycemic control and to evaluate therapeutic goals

• Values of less than 7% without adverse effect are considered desirable

• Capillary glucose testing• Testing for glucosuria and ketones



Education• Considered an essential part of diabetes

treatment• Must be tailored to the individual’s needs• Guided by national standards for the assessment,

setting of objectives, follow-up, and other areas


PEDIATRIC CONSIDERATIONS (CONT.)

Goals of Therapy• Achieving normal growth and development• Avoiding acute and chronic complications• Addressing psychosocial issues• Educating children regarding self-care



Acute Complications• Dehydration: diabetic ketoacidosis• DKA frequently precipitated by illness• When blood glucose is >240 mg/dl or during

illness, test for ketones• Hypoglycemia may be difficult to detect; subtle

behavioral changes



Chronic Complications• Rarely manifested before adolescence• Screening for neuropathy and nephropathy

should be ongoing• Counseling on metabolic control before initiation

of pregnancy



Treatment• Insulin requirements are typically 1unit/kg/day• Caloric intake must be adequate to meet needs

for energy expenditure, growth, and maturation

• Child and family need ongoing education and support to develop effective strategies toward reaching desired goals


GERIATRIC CONSIDERATIONS

Goals of Therapy• Prevention and management of acute and chronic

complications• Attention to psychosocial issues• Education regarding self-care


GERIATRIC CONSIDERATIONS (CONT.)

Acute Complications• Hyperglycemia: often asymptomatic;

dehydration; increased risk of infection; HHNK coma

• Hypoglycemia can lead to injury



Chronic Complications• Heart and blood vessel disease• Foot problems• Visual disabilities• Kidney disease



Treatment• Oral agents should be chosen carefully with

consideration of renal and hepatic function• Short-acting agents are preferable• Insulin therapy may require adaptive devices• Exercise and meal planning are advised