Pathophysiology: Diabetes mellitus PART 2

Type 1 Diabetes: Treatment, insulin profiles

- Short acting and intermediate (eg., NPH) insulin in different combinations to achieve insulin profiles as close as possible to normal insulin secretion - A newer regimen consists of monomeric and ultralente insulins - Continuous Subcutaneous Insulin Infusion + Meal Injections (rapid/short)

Type 2 diabetes: Etiology

-90-95% of cases of diabetes mellitus Rapid increase in prevalence: 'epidemic' -Population is aging -Obesity epidemic -Sedentary lifestyles -High risk ethnicities: Aboriginal, Hispanic, Asian, South Asian or African descent -Largest increase in developing countries -Obesity and type 2 diabetes in children and adolescents: 'an evolving epidemic' -Stress (hypothalamic-pituitary-adrenal axis: INCREASE cortisol/catecholamines) -Interplay between genetics and environment -Lack of sleep slide 26!!

Signs and symptoms of hypoglycemia

-Anxiety, uneasiness -Irritability -Confusion -Pale, moist skin (cold sweat) -Palpitations -Strong, rapid pulse -Dark circles under eyes -Extreme hunger -Nausea -Loss of motor coordination -Double vision -Convulsions > loss of consciousness > permanent neuronal damage if glucose is not given immediately

Education

-Blood glucose monitoring -Urine ketone monitoring -Drug onset, peak -Short- and long-term complications to monitor -When to call the provider, enter the hospital -Diet and exercise plan

Environmental factors contributing to obesity epidemic

-Energy imbalance (energy intake>energy expenditure) -Food availability/processing -Fast food -Portion over-sizing -Lack of sleep -Stress (central obesity) -Lack of exercise -Extensive screen time -Environmental stressors (e.g. low SES, unemployment) -Smoking

Type 2 diabetes: pathophysiology: pregnancy, childhood obesity and diabetes - EPIGENETICS

-Maternal-fetal environment (intrauterine) and early infancy can adversely affect the developing fetus in early life, predisposing the offspring to pediatric obesity -Maternal pre-pregnancy weight status, gestational weight gain & nutritional intake during pregnancy -Barker's 'thrifty phenotype' hypothesis: linking low birth weight with increase risk of developing type 2 diabetes mellitus and the metabolic syndrome in adulthood

Goals of Treatment

-Normalize blood glucose Blood glucose targets Minimize hypoglycemic events -Keep HbA1c <6.5.0% Reflects glucose level over past 2-3 months HbA1c increases 1% for each increase of 30 mg% in blood glucose -Avoid acute and chronic complications

Bariatric surgery for the morbidly obese patients

-Significant weight loss -Type 2 diabetes mellitus often resolved -Decreased morbidity and mortality -Some complications/problems associated with this type of surgery

Type I Diabetes Mellitus: Diagnosis

-Typically people (mostly children) with type I DM (immune-mediated) are not overweight and have recent weight loss, polyuria and polydipsia -Acute onset of signs and symptoms -Glycosuria, polyuria and frequently ketosis - Acetone - sweet, fruity breath -Often - other autoimmune diseases, such as: hypothyroidism, vitiligo, and pernicious anemia (vitamin B12 deficiency)

Pathogenesis of Diabetes Mellitus: The most important causes of DM

-an absolute deficiency of insulin (e.g., lack of beta cells secondary to islet cell destruction) -interference with insulin binding to target tissues (e.g., tissue resistance to insulin) type 2? -a relative deficiency of insulin (e.g., when the demand for insulin exceeds the supply)

Benefits of exercise for type 2 diabetes

-increase insulin sensitivity -Improved glucose tolerance -Improved control of body weight -Reversed insulin resistance resulting from obesity (exercise may the number of insulin receptors and glucose transporters) -Reduced risk factors for atherosclerosis (i.e., increase in high density cholesterol) Improved blood flow -increased conversion of fast-twitch glycolytic fibres to fast-twitch oxidative fibres, which are more sensitive to and receptive to insulin

Type 1 Diabetes: Treatment, new therapies

1. Intradermal insulin: traditional 2. Implantable pumps -usually intraperitoneal infusion (some portal absorption) 3. Closed loop systems - continuous glucose monitoring - implantable pump - feedback algorithm 4. Pancreas transplantation - usually in conjunction with a kidney transplant 5. Islet transplant - fresh islets give best success rate: multiple transplants but minor surgery; improved immunosuppresants (e.g., tacrolimus) -Xenotransplants (non-human sources of islets: e.g., pig, fish) but need to be coated with membrane - engineered cells 6. Promoting new formation, by differentiation from stem cells in pancreatic ducts, is a new potential therapeutic strategy

Type 2 diabetes pathophysiology: dysfunctional adipose tissue

A. High concentration of FFA leads to hyperinsulinemia, glucose intolerance and hypertriglyceridemia B. The adipocyte endocrine organ adipokines contribute to insulin resistance C. Inability of subcutaneous fat aka 'the metabolic sink' to expand (lipodystrophy) because it has become insulin resistant/ dysfunctional slide 31

Type 1 diabetes mellitus

Absolute lack of insulin due to β cells destruction!! -Classification -Etiology -Pathogenesis -Diagnosis -Treatment -Complications

Diabetes Prevalence

Canadian Diabetes Association states: -Currently, 285 million affected worldwide, estimated 438 million by 2030 -In Canada >3 million have diabetes mellitus -10% of people with Diabetes mellitus have type 1 diabetes -Dramatic increase of type 2 diabetes due to obesogenic society

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Chronic Somogyi rebound, also called the Somogyi effect and posthypoglycemic hyperglycemia, is a rebounding high blood sugar that is a response to low blood sugar.[1] When managing the blood glucose level with insulin injections, this effect is counter-intuitive to insulin users who experience high blood sugar in the morning as a result of an overabundance of insulin at night. Dawn phenomenon, sometimes called the dawn effect, is an early-morning (usually between 2 a.m. and 8 a.m.) increase in blood sugar (glucose) relevant to people with diabetes.[1] It is different from Chronic Somogyi rebound in that dawn phenomenon is not associated with nocturnal hypoglycemia. It is possible that dawn phenomenon is caused by the release of counterregulatory hormones such as growth hormone, cortisol, glucagon, or epinephrine, all of which can signal the liver to release glucose. Other causes may include insufficient insulin administration the night before, incorrect medication dosages, or eating carbohydrate snacks at bedtime.

more stuff on type 1 DM

Currently, autoimmunity is considered the major factor in the pathophysiology of type 1 DM. Prevalence is increased in patients with other autoimmune diseases, such as Graves disease, Hashimoto thyroiditis, and Addison disease. Prevalence of type 1 diabetes autoantibodies and newly diagnosed type 1 diabetes is higher in patients with autoimmune thyroiditis. Beta cell destruction carried by T lymphocytes and macrophages. Recent evidence suggests a role for vitamin D in the pathogenesis and prevention of diabetes mellitus. Vitamin D deficiency is also an important independent predictor of development of coronary artery calcification in individuals with type 1 DM.[5] Joergensen et al determined that vitamin D deficiency in type 1 diabetes may predict all causes of mortality but not development of microvascular complications.[6] The contribution of vitamin D deficiency to mortality must be mediated by nonvascular mechanisms. Small % of type 1 diabetes - idiopathic (no antibodies)

Diabetes Mellitus

Diabetes from a Greek - "to pass through" (because of polyuria - large amounts of urine) Mellitus - to indicate that the urine is SWEET Diabetes mellitus is a consequence of an absolute or relative insulin deficiency or abnormal response of target tissues to insulin. a heterogenous group of systemic disorders characterized by: 1. hyperglycemia 2. complex disturbances of CHO, FAT and PRO metabolism 3. variety of organic changes resulting primarily from blood vessel pathology

Exercise Recommendations for All Patients with diabetes mellitus

Exercise prescription -Modify according to person's general physical condition & lifestyle -May require modifications of standard protocols -Autonomic neuropathy may be associated with silent ischemia, postural hypotension, and/or blunted heart response Exercise program -Include warm-up & cool down, proper footwear, not in extreme heat or cold -Intensity *Aerobic: 50-85% VO2max, (moderate), more vigorous: additional health benefits *Resistance: progressively increase to 3 sets of 8 repetitions of 8 resistance-type exercises -Duration: 150 min/ week if possible, 20 - 60 min/session or accumulate several 10-min bouts daily -Frequency: 4-6 days/week total, or daily low to moderate intensity, (include aerobic 3-5 times/ week, resistance exercise 2 times/ week) -Type 2 diabetes: maximize caloric expenditure if obese

Diabetes mellitus: Complications (con't)

Eyes - diabetic microangiopathy (retinopathy) causing microaneurysmal dilations, microinfarcts with hemorrhage, and, in most severe cases, reactive proliferation with vascular sprouts; glaucoma and cataracts - Leading cause of blindness in adults - diabetic retinopathy Nervous system - microangiopathy (wide-spread focal ischemia); strokes; peripheral neuropathy Major cause of nontraumatic amputations of the toes, feet, and leg Retinopathy and neuropathy - associated with thickening of basement membranes of capillaries. Autonomic and sensory neuropathies. Autonomic: urinary bladder dysfunction, tachycardia, postural hypotension, sexual dysfunction. Sensory: carpal tunnel, lack of sensation in feet and lower leg.

Gestational Diabetes Mellitus

Glucose intolerance during pregnancy • Hyperinsulinemia > increased fetal fat deposition > macrosomia (increased fetal fat deposition = high birth weight of the child) and hypoglycemia • Increased metabolic rate may lead to fetal hypoxia, polycythemia and Respiratory Distress Syndrome • Managed with good glucose control - avoid high birth weight, hypoglycemia • Likely to reoccur in subsequent pregnancies • Increased risk of developing type 2 diabetes Prevalence rates are higher in black, Hispanic, Native American, and Asian women than in white women. For example, typically, only 1.5-2% of white women develop gestational diabetes mellitus, whereas Native Americans from the southwestern United States may have rates as high as 15%. In Hispanic, black, and Asian populations, the incidence is 5-8%. Hispanic women have higher rates of macrosomia and birth injury than women of other ethnicities, even with aggressive management. Infants of mothers with preexisting diabetes experience double the risk of serious injury at birth, triple the likelihood of cesarean delivery, and quadruple the incidence of newborn intensive care unit (NICU) admission. Studies indicate that the risk of these morbidities is directly proportional to the degree of maternal hyperglycemia.

Know the Difference!

HIGH BLOOD SUGAR -↗ thirst and ↗ urination, -ketones in urine, -aching, weak, -heavy breathing, -nausea, vomiting, -fatigue, blurred vision LOW BLOOD SUGAR Cold sweats, headache, trembling, pounding heart, sleepiness, personality change, hunger

Type 1 diabetes: Etiology (causes) cont.

Inherited susceptibility • Strongest linkage: - human leucocyte antigen (HLA) genes in the MHC (major histocompatibility complex) - 95% Type 1 diabetics carry HLA-DR3 / DR4 • other weaker links found Islet cell antibodies -A specific and sensitive predictive marker for the development of Type 1 diabetes Gene-environment interactions -Vitamin D deficiency Diabetogenic viruses • Infection of B-cells - cytomegalovirus (CMV) • Systemic infection with cross-reacting immune response - Mumps - Chickenpox - Cocsackie B - Measles - Rubella Dietary factors (early weaning in infants)? • Cow milk proteins (TRIGR) - bovine serum albumin sequence (molecular mimicry) • Other dietary components , e.g., wheat (gluten) (mainly in animal models)

Type 1 Diabetes: Treatment of ketoacidosis

Initial Treatment -Fluids (rehydration) -Electrolytes / Potassium -Bicarbonate (if pH<6.9) -Insulin injection

Type 1 diabetes: Treatment

Insulin replacement therapy - subcutaneous insulin injections - continuous subcutaneous insulin infusion (CSII) • Glucose monitoring - historical: glycosuria - glucometers (fasting glucose + other determinations) - glycated hemoglobin: hemoglobin A1c - an index of (weighted) long term control (~3months) - fructosamine and glycated albumin (~2-3 weeks) • Diet and Exercise • Education / Stress management

Type I Diabetes: Pathologenesis

Islets of Langerhans destruction and beta cells loss: INCREASE Blood glucose concentration: decreased uptake + INCREASE production (gluconeogenesis) + INCREASE release from the liver (glycogenolysis)= hyperglycemia (maintained by overproduction of glucagon) -Loss of glucose in urine = glycosuria (peeing) -Glycosuria causes dehydration leading to polydipsia (drink) -Cellular inability to get glucose - polyphagia (eating) INCREASE utilization of fats (lipolysis) - weight loss INCREASE FA and conversion of fatty acids to ketone bodies: - fruity breath - diabetic acidosis > diabetic coma Depletion of body proteins - INCREASE utilization of body proteins - loss of lean body mass

Diabetes mellitusof both types: Complications

Kidneys -Microangiopathy, renal ischemia, tubular atrophy, and interstitial fibrosis, infections -Leading cause of renal disease and kidney failure (nephropathy) Cardiovascular system -Promotes development of atheromateous plaques, formation of aneurysm, and gangrene ~ 80% of people with diabetes will die of heart disease or stroke - increase incidence of high blood pressure, elevated cholesterol, LDL, and triglycerides

MODY

MODY - autosomal, defect in production of insulin; -mild hyperglycemia and hyposecretion of insulin; -defect but no loss of B-cells of Langerhans and no loss of insulin sensitivity, -no ketosis; -treatment with sylfonyureas. -MODY has an earlier onset than most of type 2 diabetes mellitus cases. -MODY is sometimes compared to type 2 diabetes, and shares some type 2 diabetes symptoms. -However, MODY is not linked to obesity, and typical MODY patients are young and not necessarily overweight.

Type 2 diabetes: pathophysiology

Obese people have ↗ ↗ ↗ FFA Hypothesis: • ↗ FFA contribute to insulin resistance (genetically predisposed obese people) - too little glucose enters peripheral tissues - glucose accumulates in blood ↗ FFA stimulate greater insulin secretion = hyperinsulinemia (β cells compensate for insulin resistance) and blood plasma glucose levels are temporarily under control • This eventually leads to β cells failure, inadequate insulin production and hyperglycemia • Hyperglycemia makes β cell failure worse and leads to a vicious cycle

Type 2 diabetes: additional diagnostic criteria

Overweight or obese Plus any two of the following risk factors: -Family history of type II diabetes in first- or second-degree relative -Race/ethnicity (American Indian, African-American, Hispanic, Asian/Pacific Islander) -Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, Polycystic ovary syndrome) *Ecessive insulin can cause change in features. *acanthosis nigricans on back of neck

What to do if a person becomes hypoglycemic?

Patient CONSCIOUS -Stop the activity immediately -Have the person sit down and check blood glucose level -Have the person eat high-glycemic index (GI) carbohydrates such as dextrose tablets, sugar, candies, honey, or drink soft drinks such as coca-cola (regular, NOT diet!!!), fruit juices, milk -Allow a person to rest and wait for response -Check blood glucose level -If no improvement - treat with simple carbohydrates again -When a person feels better, have him/her consume a sandwich or other source of complex carbohydrates with lower GI -When the sugar stabilizes resume the activity -Frequent glucose monitoring important Patient UNCONSCIOUS - iv glucose, glucagon Frequent glucose monitoring important!!!!!

Type 2 diabetes mellitus

Relative lack of insulin due to insulin resistance and β cells dysfunction.

Glucose homeostasis in a healthy person and unhealthy person PICTURES

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Type I diabetes: PathogenesisHyperglycemia and hyperosmolar coma

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Type 2 diabetes: pathogenesis

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The dawn phenomenon

The dawn phenomenon (the dawn effect) - an abnormal early-morning increase in blood glucose — usually between 2 a.m. and 8 a.m. — in people with diabetes mellitus Research indicates that it is due to: *overnight release of hormones — including growth hormones, cortisol, glucagon and epinephrine that increase insulin resistance, causing blood sugar to rise. *insufficient insulin the night before or incorrect medication dosages *carbohydrate snack consumption at bedtime

more on epigenetics

The idea that epigenetic changes associated with chromatin remodeling and regulation of gene expression underlie the developmental programming of metabolic syndrome is gaining acceptance. Converging data are now available to support the hypothesis that, in addition to "thrifty genotype" inheritance, individuals with metabolic syndrome underwent incorrect "epigenetic programming" during fetal/postnatal development because of inadequate maternal nutrition and metabolic disturbances. These individuals may also display "transgenerational effects" because of the inheritance of epigenetic changes first experienced by their parents and/or grandparents.

Type 1 DM classification

Type A1: Immune -polygenic -monogenic -LADA *Most have polygenic Type B: Idiopathic

Increase in plasma insulin concentrationafter a sudden increase in blood glucose

Under normal conditions - insulin secreted in two phases In type 2 diabetes, even though lots of insulin is produced, the first phase is lost this has a major effect on insulin action With time - second phase also decreases SLIDE 29

Gestational Diabetes Mellitus continued

Untreated gestational diabetes may result in metabolic abnormalities and stillbirth The most common complications are: macrosomia (birth weight > 4 kg) hypoglycemia 1. placenta oroduces hormones (estrogen, cortisol and human placental lactogen) 2. these hormones inhibit the functioning of insulin 3. blood glucose level is increased Believed that hormones for preg. Interfere with sensitiveity of receptors, cause hypoglycemia.

Primary Diabetes Mellitus

accounts for most cases! -Type 1 diabetes mellitus (autoimmune disease) -Type 2 diabetes mellitus (generally polygenic=many genes affected) -Maturity Onset Diabetes Mellitus of the Young (MODY) - B cells of Langerhans defect (single gene defect) (being overweight is associated) =less production of insulin -Latent Autoimmune Diabetes of Adults (LADA) - >failing B cells of Langerhans (slowly progressing to type 1 diabetes mellitus) gradually less insulin is produced

Secondary Diabetes Mellitus

forms of diabetes that can be traced to some other diseases; Examples: >Pancreatic diseases (chronic pancreatitis), hyperactive pituitary >Diseases of the endocrine glands -Acromegaly - anti-insulin-like effect of excess growth hormone -Cushing's syndrome - cortisol oversecretion leadingto ↗ gluconeogenesis & ↙ peripheral glucose utilization -Hyperthyroidism -Glucose hypersecretion (e.g., tumors of A-cells causing increased glucagon secretion and increased gluconeogenesis) >Drug or chemical induced diabetes mellitus - e.g, corticosteroid treatment of severe asthma 3) Gestational diabetes mellitus (sedentary) 4) Other types of diabetes mellitus

Type 1 diabetes: Etiology (causes)

genetic factors/ environmental factors >>Autoimmune destruction of beta cells> insulin deficiency> other metabolic disturbances/ hyperglycemia slide 12

Type 1 Diabetes acute problems (type 1 and insulin-dependent type 2 diabetes)

hypoglycemia = insulin reaction Main causes • mismatch of food and insulin • strict blood glucose control • long duration of diabetes • hypoglycemia unawareness • exercise (without proper glucose monitoring) • alcohol and other drugs (insulin, sulfonylureas)

Type 1 Diabetes Mellitus - Diagnostic Criteria

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The Postulated Sequence of Events Leading to Insulin Resistance and decreased peripheral glucose intake

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factors reducing rsponse to insulin

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Glucose homeostasis in the person with type 2 diabetes mellitus

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Type 2 Diabetes Mellitus - Diagnostic Criteria

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Glucose tolerance curve in a normal personvs. a person with type 2 diabetes mellitus

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Comparison of main characteristics of type I and type 2 Diabetes Mellitus

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Diagnosis of type 1 vs. type 2 diabetes mellitus

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Type 2 diabetes: Prevention & treatment

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