EHR522 weeks 5-9

Pathophysiology of Diabetes

• Insulin resistance in peripheral tissues and defective insulin secretion are common features of diabetes.
• With insulin resistance, the body cannot effectively use insulin in the muscles or liver, even though sufficient insulin is being produced.

Type II Diabetes

• Lifestyle management, including medical nutrition therapy (MNT) and physical activity, are treatment options for type II diabetes.
• Medication, including oral agents, insulin, or other injectable diabetes medications, may be needed to reach glycaemic targets if lifestyle management is not effective.
• Bariatric surgery may be added to the treatment plan for those who are obese (BMI > 35) and have unmanageable diabetes or comorbidities.
• Ketoacidosis rarely occurs in type II diabetes.
• A genetic influence is present for type II diabetes, with a 3.5-fold higher risk for offspring with one parent with type II diabetes and a 6-fold higher risk for those with two such parents.
• Obesity contributes significantly to insulin resistance, with 80% of people with type II diabetes being overweight or obese at disease onset.
• The risk of developing type II diabetes increases with age, lack of physical activity, history of gestational diabetes, and presence of hypertension or dyslipidaemia.

Gestational Diabetes

• Gestational diabetes is defined as "diabetes diagnosed in the second or third trimester of pregnancy that is not clearly either type I or type II diabetes."
• It is usually diagnosed with an oral glucose tolerance test (OGTT) performed at 24-28 weeks of pregnancy.
• Risk factors for developing gestational diabetes include family history, previous delivery of large birth weight, obesity, and other factors.
• Although glucose tolerance usually returns to normal after delivery, women who have had gestational diabetes have a greatly increased risk of conversion to type II diabetes over time.
• They are recommended to have lifelong screening for the development of diabetes or pre-diabetes at least every three years.
• Structured moderate physical exercise training during pregnancy decreases the risk of gestational diabetes, diminishes maternal weight gain, and is safe for the mother and neonate.

Other Specific Types of Diabetes

• In other specific types of diabetes, certain diseases, injuries, infections, medications, or genetic syndromes cause the diabetes.
• This type may or may not require insulin treatment.

Complications of Diabetes - Acute Complications

• The acute complications of diabetes are hyperglycaemia (high blood glucose) and hypoglycaemia (low blood glucose).
• Each of these acute complications must be quickly identified to ensure proper treatment and reduce the risk of serious consequences.
• The manifestations of hyperglycaemia include poorly managed blood glucose levels, diabetic ketoacidosis, and hyperosmolar non-ketotic syndrome.
• High blood glucose levels cause the kidneys to excrete glucose and water, leading to increased urine production and dehydration.
• Symptoms of hyperglycaemia and dehydration include headache, blurred vision, increased thirst, weakness, and fatigue.
• The best treatment for anyone with frequently elevated blood glucose levels includes drinking plenty of non-carbohydrate-containing beverages, regular self-monitoring of blood glucose, and, when instructed by a health care professional, increasing diabetes medications.
• Frequent high blood glucose levels damage target organs or tissues over time, increasing the risk of chronic complications.

Prevention and Treatment of Abnormal Blood Glucose

• Those with type II diabetes who are appropriately managed by diet and exercise alone usually experience a reduction in blood glucose level with low to moderate exercise.
• Timing of exercise after meals can help many patients with type II diabetes reduce post-prandial hyperglycaemia.
• Blood glucose should be monitored after an exercise session to determine the patient's response to exercise.
• Patients are more likely to experience hypoglycaemia (usually < 3.6 mmol/L) after exercise than during due to post-exercise replacement of muscle glycogen, which uses blood glucose.
• Periodic monitoring of blood glucose is necessary in the hours following exercise to determine whether blood glucose is dropping.
• More frequent monitoring is especially important when initiating exercise.
• In poorly controlled diabetes, insulin levels are often too low, resulting in an increase in counter-regulatory hormones with exercise, especially when the exercise is vigorous.
• This can cause an increase in blood glucose level during and after exercise.

Cardiorespiratory and Resistance Exercise

• Benefits for persons with diabetes are seen with both acute and chronic cardiorespiratory and resistance exercise training.
• Acute bouts of exercise can improve blood glucose, particularly in those with type II diabetes.
• The response of blood glucose to exercise is related to pre-exercise blood glucose levels as well as to the duration and intensity of exercise.
• The effect of acute exercise on blood glucose levels in those with type I diabetes and in lean patients with type II diabetes is more variable and unpredictable, but glycaemic benefits are still possible with concomitant dietary management.
• A rise in blood glucose with exercise can be seen in patients who are extremely insulin deficient (usually type I) and with short-term, high-intensity exercise.
• Most of the benefits of exercise for those with diabetes of any type come from regular, long-term exercise.
• These benefits can include improvements in metabolic control, hypertension, lipids, body composition, and weight loss or maintenance, as well as psychological well-being.
• Both the frequency of aerobic training and the volume of resistance training appear to be important in lowering overall blood glucose levels in type II diabetes.
• Like acute exercise, exercise training can improve blood glucose.
• Exercise training (both aerobic and resistance) improves glucose control as measured by HbA1c or glucose tolerance, primarily in those with type II diabetes.
• Following exercise training, insulin-mediated glucose disposal is improved, and insulin sensitivity of both skeletal muscle and adipose tissue can improve with or without a change in body composition.
• Exercise may improve insulin sensitivity through several mechanisms, including changes in body composition, muscle mass, fat oxidation, capillary density, and glucose transporters in muscle (GLUT4).

Polycystic Ovarian Syndrome (PCOS)

• PCOS is an endocrinopathy of uncertain aetiology, affecting 4-20% of women of reproductive age
• Features of PCOS can be broadly divided into three categories: clinical, endocrine, and metabolic

Clinical Features of PCOS

• Menstrual abnormalities (oligomenorrhea or amenorrhea)
• Hirsutism
• Acne
• Alopecia
• Anovulatory infertility
• Recurrent miscarriages

Endocrine Features of PCOS

• Elevated androgens
• Elevated luteinising hormone
• Elevated oestrogen
• Elevated prolactin

Metabolic Features of PCOS

• Insulin resistance
• Obesity
• Lipid abnormalities
• Increased risk for impaired glucose tolerance and T2DM

Prevalence of Common Features of PCOS

• Menstrual disturbances: 30% of women with PCOS have normal menses
• Oligomenorrhea and amenorrhea: 85-90% of women with PCOS
• Infertility: 40% of women with PCOS
• Anovulatory women presenting to infertility clinics: 90-95% have PCOS
• Spontaneous abortion: 42-73% in women with PCOS

Risk Factors for PCOS

• T1DM
• T2DM
• GDM

Common Comorbidities of PCOS

• Insulin resistance: 50-70% of women with PCOS
• Metabolic syndrome
• Hypertension
• Dyslipidaemia
• Glucose intolerance
• Diabetes
• Mental health disorders: depression, anxiety, bipolar disorder, binge eating disorder

Diagnostic Criteria for PCOS

• At least two of the following characteristics in the absence of other causes:
  • Clinical or biochemical hyperandrogenism
  • Anovulatory menstrual dysfunction
  • Polycystic ovaries on ultrasound

Pathophysiology of PCOS

• The heterogeneity of PCOS may represent multiple pathophysiological mechanisms
• Theories of pathogenesis:
  • Unique defect in insulin action and secretion
  • Primary neuroendocrine defect
  • Defect of androgen synthesis
  • Alteration in cortisol metabolism

Economic Burden of PCOS

• $4.4 billion annually in the USA healthcare system
• 40% attributed to treating reproductive dysfunction (infertility and menstrual dysfunction)
• 40% attributed to PCOS-related diabetes

Pharmaceutical Intervention for PCOS

• Focuses primarily on addressing reproductive dysfunction and insulin resistance
• Oral contraceptives for menstrual irregularity, hirsutism, and acne
• Spironolactone (aldosterone antagonist) and finasteride (5-alpha reductase inhibitor) for symptoms of androgen excess
• Fertility treatments: ovulation induction agents (Clomiphene Citrate), exogenous gonadotropins, laparoscopic ovarian drilling, and assisted reproductive technology
• Metformin for insulin resistance and ovulation induction

Exercise Intervention for PCOS

• Individualised exercise prescription based on presentation and clinical features/comorbidities
• Improvements in:
  • Follicle-stimulating hormone
  • Sex hormone-binding globulin
  • Decreased total testosterone
  • Decreased androstenedione
• Weight loss: successful in some studies, but not all
• Insulin resistance: approximately half of available studies demonstrate improvement with exercise intervention
• Blood lipids: limited studies demonstrate improvements in triglycerides, HDLc, and LDLc with exercise intervention
• Blood pressure: approximately half of available studies demonstrate reduction in systolic or diastolic blood pressure with exercise intervention
• Reproductive function: three out of five studies report improvements in menstrual and/or ovulation frequency with exercise intervention

Obstructive Sleep Apnea (OSA)

• Associated with conditions such as hypertension, CVA, MI, cor pulmonale, and motor vehicle accidents
• Physical examination can suggest increased risk and should include evaluation of respiratory, cardiovascular, and neurological systems

Physical Examination

• Features to evaluate:
  • Increased neck circumference (> 17 inches in men, > 16 inches in women)
  • BMI ≥ 30
  • Modified Mallampati score of 3 or 4
  • Presence of retrognathia, lateral peritonsillar narrowing, macroglossia, tonsillar hypertrophy, elongated or narrow hard palate, and nasal abnormalities

Objective Testing

• Two accepted methods: in-laboratory polysomnography and home testing with portable monitors
• Portable monitors can diagnose OSA when used as part of a comprehensive sleep evaluation in patients with high pre-test likelihood of moderate to severe OSA
• Polysomnography requires recording of:
  • Electroencephalogram (EEG)
  • Electrooculogram (EOG)
  • Chin electromyogram
  • Airflow
  • Oxygen saturation
  • Respiratory effort
  • Electrocardiogram (ECG) or heart rate
• Additional recommended parameters: body position and leg EMG derivations
• Portable monitors should record:
  • Airflow
  • Respiratory effort
  • Blood oxygenation

Categorization of Severity

• Severity of OSA is based on the number of apnoea or hypopnoea events per hour of sleep, represented by the Apnoea Hypopnoea Index (AHI)
• Parameters for OSA:
  • Normal: AHI < 5
  • Mild: AHI ≥ 5 and < 15
  • Moderate: AHI ≥ 15 and < 30
  • Severe: AHI ≥ 30

Treatment - PAP

• American Academy of Sleep Medicine recommends use of continuous positive airway pressure (CPAP) or oral appliances for treating mild to moderate OSA
• CPAP is recommended as the first-line, and oral appliances as second-line, treatments for severe OSA
• PAP provides pneumatic splinting of the upper airway and is effective in reducing the AHI
• Modes of PAP: continuous (CPAP), bilevel (BPAP), autotitrating (APAP), and partial pressure reduction during expiration (pressure relief)

Treatment - Behavioral Strategies

• Behavioral treatment options:
  • Weight loss
  • Exercise
  • Positional therapy
  • Avoidance of alcohol or sedatives before bedtime
• Successful dietary weight loss may improve the AHI in obese patients with OSA
• Positional therapy can improve the AHI by keeping the patient in a non-supine position

Treatment - Oral Appliances

• Custom-made oral appliances can improve upper airway patency during sleep by enlarging the upper airway and/or decreasing upper airway collapsibility
• Types of oral appliances:
  • Mandibular repositioning appliances (MRA)
  • Tongue retaining devices (TRD)

Treatment - Surgical

• Surgical therapy includes upper airway reconstructive or by-pass procedures, often site-directed and/or staged
• Evaluation for primary surgical treatment can be considered in patients with mild OSA who have severe obstructing anatomy that is surgically correctible
• Surgical procedures may be considered as a secondary treatment for OSA when the outcome of PAP therapy is inadequate

Adjunctive Therapies - Bariatric Surgery

• Bariatric surgery is an effective means to achieve major weight loss and is indicated in individuals with a BMI ≥ 40 or those with a BMI ≥ 35 with important comorbidities and in whom dietary attempts at weight control have been ineffective
• Remission rate for OSA two years after bariatric surgery is 40%

Adjunctive Therapies - Pharmacotherapy and Supplemental Oxygen

• There are no widely effective pharmacotherapies for OSA, with the exception of individuals with hypothyroidism or acromegaly
• Oxygen supplementation is not recommended as a primary treatment for OSA
• Modafinil is recommended for the treatment of residual excessive daytime sleepiness in OSA patients who have sleepiness despite effective PAP treatment and who are lacking any other identifiable cause of their sleepiness

A Role for Exercise?

• Very few RCTs available that analyze the role of exercise in the management of OSA
• Meta-analysis of limited available studies shows that exercise in OSA:
  • Decreases AHI
  • Reduces Epworth Sleepiness Scale
  • Has minimal or no reduction in BMI
• Exercise has been shown to reduce the severity of other disorders and/or diseases associated with OSA, including diabetes, CVD, hypertension, and obesity
• It is not fully understood how exercise reduces OSA symptoms, but research indicates that the impact of exercise on OSA is not related to a reduction in body mass or BMI

Medications in Metabolic Disease

Biguanides

• Metformin is an example of a biguanide medication
• Decreases hepatic glucose production
• May also improve insulin resistance in muscles
• Very low risk of hypoglycemia (possibly after prolonged strenuous exercise)
• Not used in patients with abnormal creatinine clearance (CHF and CKD)

Sulfonylureas (1st Generation)

• Examples include tolbutamide, tolazamide, and chlorpropamide
• Increase insulin production in the pancreas
• Carry a significant risk of hypoglycemia
• Many have a very long half-life and are typically now only used in patients with a well-established history of taking them

Sulfonylureas (2nd Generation)

• Examples include glyburide, glipizide, and glimepiride
• Increase insulin production in the pancreas
• Carry a risk of hypoglycemia (but less than that of 1st generation sulfonylureas)
• More predictable results with fewer side effects and more convenient dosing when compared with 1st generation sulfonylureas

Thiazolidinediones

• Examples include pioglitazone and rosiglitazone
• Works via multiple mechanisms
• Decrease insulin resistance, increasing glucose uptake
• Redistribution of fat
• Minor decrease in hepatic glucose output
• Preserve beta cell function
• Decrease vascular inflammation
• No significant risks with exercise, but can cause mild to moderate oedema

Alpha-Glucosidase Inhibitors

• Examples include acarbose and miglitol
• Slow the absorption of starch, disaccharides, and polysaccharides from the GI tract
• No significant risks with exercise, but can cause gas, bloating, and occasionally diarrhoea

Dipeptidyl Peptidase 4 (DPP-4) Inhibitors

• Examples include sitagliptin, saxagliptin, vildagliptin, and linagliptin
• Inhibits the DPP-4 enzyme that is responsible for degrading the incretins, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP)
• The increasing incretin levels inhibit glucagon release, which in turn increases insulin secretion and decreases BGLs
• Carry a low risk of hypoglycemia with exercise
• Not used in T1DM

Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors

• Examples include canagliflozin, dapagliflozin, empagliflozin, and erugliflozin
• Inhibit the reabsorption of glucose in the kidneys, therefore lowering BGLs
• Can increase the risk of ketoacidosis and UTI
• Can cause dehydration, so ensure patients are well-hydrated with exercise

Injected (Non-Insulin) Medications

• Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

  • Examples include exenatide, dulaglutide, liraglutide, semaglutide, and lixisenatide
  • Works via multiple mechanisms
  • Decreases post-meal glucagon production
  • Delays gastric emptying
  • Increase satiety, leading to decreased caloric intake
  • Not suitable for T1DM
  • May reduce the rate of absorption of oral medications
  • Can increase the risk of hypoglycemia when combined with a sulfonylurea

• Amylin Analogue

  • Example: pramlintide
  • Works via multiple mechanisms
  • Decreases post-meal glucagon production
  • Delays gastric emptying
  • Increase satiety, leading to decreased caloric intake
  • Indicated for insulin-treated T2DM and T1DM
  • Contraindicated in patients with hypoglycemia unawareness
  • Should not be mixed with insulin (must be injected separately)
  • Can increase the risk of hypoglycemia when combined with insulin

Insulin

• Rapid Acting Insulin

  • Do not allow patients to exercise at the peak insulin dose of a rapid acting insulin (first 2 hours following drug administration)

• Short Acting Insulin

• Intermediate Acting Insulin

• Long Acting and Ultra Long Acting Insulin