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Unit 4 Metabolism & Metabolic Disease Diabetes Mellitus Paul Anderson2009 Pathophysiology
Learning Objectives 1.Describe the origin & functions of insulin. 2.Describe the following antagonistic hormones to insulin. Glucagon, Growth Hormone, Glucocorticoids (Cortisol), Catecholamines (Epinephrine). 3.Distinguish between the various types of Diabetes mellitus. Type 1, Type 2, Type 3 (other specific types), Type 4 Gestational DM. 4. Describe the causes, manifestations, pathogenesis, treatment and complications of DM type 1. 5.Describe the causes, manifestations, pathogenesis, treatment and complications of DM type 2. 6.Describe the causes, manifestations, pathogenesis, treatment and complications of Gestational DM. References: Porth, Essentials, Ch. 17 Ch. 32 Porth, Pathophysiology, Ch. 43
Diabetes Mellitus Diabetes has been described as “the global disease of the 21st century” affecting more than 150 million people worldwide, 2 million Canadians & 500,000 Quebecers. These numbers are rising & because of our lifestyles, especially the prevalence of obesity among the young: “we are headed for a global diabetes epidemic”. The medical costs are enormous, taking about 25% of Medicare’s budget. In Quebec diabetics take 20% of hospital beds, form 25% of heart surgeries, 40% of kidney failures & 50% of amputations. Diabetes is the primary cause of dialysis & is the primary cause of adult blindness. Diabetes is a major cause of Coronary Heart Disease, Cerebrovascular Accidents & Atherosclerosis: 70 % of diabetics die from cardiovascular disease.
Origin & Functions of Insulin Insulin is an anabolic hypoglycemic hormone. Insulin is secreted into the blood by beta cells of the pancreatic Islets of Langerhans. Insulin is released by alimentary (postprandial) hyperglycemia. Insulin stimulates the uptake & usage of glucose & amino acids by target cells with the following specific actions: Increases glucose uptake by adipose, skeletal muscle, liver & many other tissues. Stimulates glycogenesis in liver & skeletal muscle. Stimulates lipogenesis & inhibits lipolysis in adipose cells. Stimulates amino acid uptake & protein synthesis by cells. Inhibits gluconeogenesis in the liver.
Functions of Insulin glycogenesis Amino acid uptake lipogenesis Protein synthesis glucose uptake to form glycerol glucose uptake Modified from Porth Essentials Figure 32-1 when sufficient glycogen stored Skeletal muscle Adipose tissue Liver glucose uptake
Structure of of ProInsulin Insulin is a peptide hormone with 51 amino acids, in 2 (A and B) chains connected in proinsulin by a C peptide that is removed in beta cells to form insulin. C peptide proinsulin C peptide is secreted with insulin & is used to study B cell activity Porth Essentials Fig 32-3 Porth, Pathophysiology, fig 43-3
Endocrine Pancreas: Islets of Langerhans Amylin aids insulin by effectively slowing the intestinal absorption of glucose & suppressing glucagon. glucagon insulin amylin Porth Essentials Figure 32-2 Porth, Pathophysiology, fig 43-2
Insulin Receptors on Target Cells Insulin receptor Insulin binds to membrane receptors of target cell Insulin activates glucose transporters Insulin activates amino acid carriers Insulin activates enzymes for anabolic pathways Porth Essentials Figure 32-5 Porth, Pathophysiology, fig 43-6
Antagonistic Hormones to Insulin Glucagon from alpha cells of the pancreatic islets released by low blood glucose and exercise, increases blood glucose by stimulating glycogenolysis, gluconeogenesis & lipolysis. Glucocorticoids (mainly cortisol ) from the adrenal cortex, secreted by hypoglycemia & by chronic stress (via ACTH) cause gluconeogenesis, fat & protein mobilisation. Epinephrine from the adrenal medulla released by acute stress (e.g. exercise) causes glycogenolysis. Growth Hormone from the anterior pituitary has a “diabetogenic action” by causing lipolysis & glycogenolysis. Insulin is the only Hypoglycemic Hormone. Hyperglycemic Hormones are antagonistic to insulin. Prolonged excessive secretion or use of Glucocorticoids or Growth Hormone can cause Diabetes Mellitus.
DM is a group of metabolic diseases characterized by hyperglycemia DM results from defects in insulin secretion, insulin action, or both. Diabetes Mellitus There are 4 types of Diabetes Mellitus Type 1 DM: due to pancreatic beta cell destruction mainly by an autoimmune process. Type 2 DM: due to combination of beta cell dysfunction and insulin resistance. Type 3 DM (“Other Specific Types”) –Secondary to other diseases, e.g. Cushings, acromegaly, pancreatitis, viral infections, genetic disorders (e.g. to beta cells). –Due to drugs (some diuretics, anti-retroviral AIDS, steroids, or toxins. Type 4 DM - Gestational Diabetes in pregnant women.
Type 1 Diabetes Mellitus Type 1 DM Occurs in 5-10% of diabetics. Type 1 DM is mostly in young persons (< 30 yrs with peak at yrs) so previously known as “Juvenile Diabetes”. cell destruction rapidly progresses in children. Type 1 DM results in insulin deficiency or absence so previously called “Insulin Dependent Diabetes”. Type 1 DM is a catabolic disorder causing fat & protein mobilisation, wt loss & often causes Ketosis. Presentation of DM Type 1 tends to be acute with manifestations of hyperglycemia,“3 polys” & ketoacidosis. Manifestations in DM type1 reflect beta cell dysfunction with near total loss of insulin production.
Type 1 Diabetes Mellitus: Manifestations Polyuria from osmotic diuresis. Polydipsia & dryness of mouth from dehydration. Polyphagia from powerful messages to eat by insulin - dependent cells of hypothalamic hunger control center. Hyperglycemia (plasma glucose >250mg/dL) causing: - Glucosuria, osmotic diuresis & dehydration (resulting in hypotension with compensatory tachycardia ). - Blurred vision and superficial infections (e.g yeast). - Electrolyte depletion & Pseudohyponatremia : K + is drawn out of cells & excreted & also lost in vomiting, net osmosis to ECF (from hyperglycemia) dilutes plasma Na +. Lethargy, weakness & fatigue from catabolism of muscle proteins & hypotension. Weight loss from osmotic diuresis, vomiting & lipolysis. Ketoacidosis if present, causes nausea, vomiting, abdominal cramps, other manifestations of acidosis & eventual coma.
Diagnosis of Diabetes Mellitus: Blood Glucose Tests Fasting Plasma Glucose is the preferred diagnostic test. FPG of >126 mg/dL (7 mmol/L) indicates DM Casual Plasma Glucose of >200mg/dL (11.1 mmol/L) indicates DM Oral Glucose Tolerance Test - measures the insulin response after glucose intake - 75g (100 g for gestational DM) of concentrated glucose given orally - Plasma [glucose] measured at 1 h & 2h (& 3h for gestational DM). - 2h plasma [glucose] of >200mg/dL indicates DM Glycated Hemoglobin (Hb)Test - Glucose enters erythrocytes & combines with Hb - The higher the blood [glucose] the greater the % of glycated (glycosylated) Hb (A1C): normal A1C 7% Diagnosis of Diabetes Mellitus requires Plasma Glucose Testing. Normal fasting plasma glucose < 100mg/dL (5.55 mmol/L
In Diabetic Ketoacidosis (DKA) –Cells are not receiving glucose/amino acids due to inadequate or no insulin. –In absence of insulin lipolysis is increased for energy (insulin inhibits lipolysis). –DKA is often preceeded by stress which triggers release of cortisol causing further fat mobilisation and gluconeogenesis. –Liver converts excess free fatty acids to ketone bodies (ketogenesis). –Ketones accumulate in blood causing ketosis & ketoacidosis. Ketoacidosis: Acute Complication of Type I Diabetes Mellitus
Low plama pH (< 7.3) Hyperventilation - increased BR & depth = Kussmaul’s respiration (respiratory compensation for metabolic acidosis). Low plasma bicarbonate (HCO 3 - ) < 25 mEq/dL due to buffering of plasma by bicarbonate. Ketonemia Ketonuria Fruity breath (due to acetone). Lethargy, nausea, vomiting & abdominal pain (note: vomiting compounds the dehydration already present). Hyperglycemia Depression of CNS causes stupor & eventual coma. Diabetic Ketoacidosis (DKA): Manifestations Ketoacidosis is a form of Metabolic acidosis
Type 1 Diabetes Mellitus Causes & Pathogenesis Caused by - genetic predisposition - environmental trigger, e.g. viral infection. Genes involved are on chromosomes 6 & chromosome 11 (for beta cell division & function). 2 types of auto-antibodies identified: anti - Insulin and anti- islet antibodies. Autoantibody testing identifies 85 % of cases of DM1 with 98% specificity. T-cell triggering events may involve exposure to environmental substance similar to the auto antigen. The activated T- cell then attacks beta cells. Hyperglycaemia itself causes further beta cell destruction.
Type 1 Diabetes Mellitus Treatment Treatment of type 1DM usually involves exogenous Human Insulin Replacement Therapy. Since insulin is destroyed in the GI tract it must be injected. To simulate the normal pattern of insulin secretion multiple daily injections (MDIs) or continuous subcutaneous infusion of insulin (CSII) are used. Exogenous Insulin has the potential to induce potentially serious hypoglycemia so must be carefully controlled. Amylin analogue is a new injectible anti diabetic agent for type 1 DM. Amylin aids insulin by effectively slowing intestinal absorption of glucose. Treatment of Diabetic Ketoacidosis (DKA ) involves restoring plasma volume, blood glucose, pH & electrolyte balance by administering insulin with IV fluid & electrolyte replacement. Treatment of Type 1 DM with insulin may initially result in a “honeymoon” period where the patient can manage without insulin due to beta cell regeneration.
Hypoglycemia: An Acute Complication of Type I Diabetes Mellitus Hypoglycemia typically occurs from an overdose of insulin or other hypoglycemic agent in Type 1 DM. Hypoglycemia may be precipitated by exercise, failure to eat or use of alcohol Symptoms show rapid onset, are progressive & are due to - effects of hypoglycemia on CNS - compensatory activation of sympathetic NS.
Effect of Hypoglycemia on CNS -Shakiness- Dizziness- Hunger- Headache -Sudden moodiness or behavior changes -Clumsy or jerky movements -Difficulty paying attention, or mental confusion - Tingling sensations around the mouth (paresthesia) - Anxiety - Seizures - coma Hypoglycemia: Manifestations Compensatory Activation of Sympathetic NS - Pale cool, clammy skin - Sweating - Tachycardia
Type 2 Diabetes Mellitus Most diabetics are type 2 ( %). DM2 is mostly in adults over 40 yrs but recent increasing incidence in obese adolescents & children. Canadian Diabetes Association advises screening people over 40 every 3 yrs. Genetic predisposition with x increased risk if family history (>25% chance if first degree relative, with concordance in twins of %).
Obesity - 85% of DM 2 patients are obese so combination now called “diabesity”. - obesity tends to be present with other signs of “Metabolic Syndrome” (high blood TGs, low blood HDLs, hypertension, systemic inflammation & atherosclerosis). Lack of physical activity - exercise causes wt loss & increases insulin sensitivity. - moderate daily exercise for 30 mins coupled with a % wt loss reduces diabetes risk by 58%. Increased Body Mass Index (BMI) of >25 - BMI is a measure of body fat content BMI = wt in kg/(ht in meters, squared). Increased abdominal fat = waist circumference - health risk for males if >40” (102 cm). - health risk for females) if >35” (88 cm). Type 2 Diabetes Mellitus: Risk Factors e.g. woman ht 1.6m wt 50kg BMI = ? Answer: normal
Type 2 Diabetes Mellitus: Causes of Metabolic Abnormalities High levels of FFAs have 3 harmful effects: Peripheral Insulin Resistance FFAs chronically stimulate beta cells causing disturbed insulin secretion & eventually causing exhaustion of beta cells and failure to secrete adequate amounts of insulin. FFAs reduce hepatic insulin sensitivity resulting in increased output of glucose from liver. Major metabolic abnormalities in DM 2 are probably caused by: Genetic Predisposition Increased levels of circulating Free Fatty Acids (FFAs) from diet or from lipolysis in enlarged adipocytes in obese persons.
Type 2 Diabetes Mellitus: Pathogenesis From Porth Essentials Figure 32-7 Porth, Pathophysiology fig 43-7 FFAs cause peripheral insulin resistance FFAs cause cell failure FFAs reduce hepatic response to insulin Hyperglycemia Diabetes Type 2 insulin resistance hepatic glucose output (gluconeogenesis) deranged insulin secretion Genetic predisposition Environmental Risk Factors Obesity
Type 2 Diabetes Mellitus: Manifestations Type 2 DM often presents insidiously with no symptoms in its early stages & then with many of the gradually developing manifestations related to hyperglycemia that are present in Type 1 DM. Blurred vision, parasthesias, and superficial skin infections (e.g yeasts such as vaginal candidiasis) from chronic hyperglycemia are often the earliest non specific manifestations of Type 2 DM. These manifestations indicate that the person already has Insulin Resistance and Reduced Insulin Secretion.
Type 2 Diabetes Mellitus vs Type 1 Diabetes Unlike Type 1 DM In Type 2 DM only “2 Polys” usually present, - Polyuria & Polydipsia (with dryness of mouth). - Polyphagia is not common in DM type 2. In Type 2 DM Ketosis (and DKA) are not common as some insulin is present so there is less reliance on fatty acids & ketone bodies for energy than in DM type 1. In Type 2 DM obesity is usually present (as a risk factor) instead of the weight loss (as a manifestation) seen in Type 1 DM.
Treatment of Type 2 Diabetes Diet Management Weight Loss Exercise Oral Antidiabetic Agents (some also used to treat Type 1 DM) have 4 types of action: - Reduce liver glucose output (e.g. metformin). - Stimulate Beta cells (only for Type 2 DM) e.g. sulfonylureas, increase insulin release after eating. Some may cause hypoglycemia. - Delay carbohydrate absorption from intestine, e.g. amylin analogue, inhibitors of intestinal debranching enzyme ( glucosidase inhibitors). - Increase insulin sensitivity of insulin dependent target tissues (adipose, muscle, liver) for Type 2 DM, e.g. TZDs.
Drug reduces glucose output by liver Drug increases insulin dependent glucose uptake of target cells. Actions of Antidiabetic Drugs in Type 2 DM Drugs prevent hyperglycemia Drug stimulates beta cells to secrete more insulin Drug delays absorption of glucose From Porth Essentials Figure 32-8A Porth, Pathophysiology fig 43-8A
Acute Complication of Type 2 Diabetes Mellitus: Hyperglycemic Hyperosmolar State HHS is a serious acute complication of Type 2 Diabetes Mellitus & indicates a worsening of the disease. HHS is usually seen in elderly patients after eating a meal containing high levels of carbohydrates. Manifestations include - Extreme hyperglycemia of > 600 mg/dL causing extreme hyperosmolarity of > 310 mOsm/L, without ketosis. - Polyuria causing extreme dehydration, thirst & serious K deficit. - Neurological signs include seizures, aphasia (inability for speech), hallucinations, fasciculations (muscle twitching), visual disturbances. Coma & death occurs in % of patients. Treatment consists of carefully controlled rehydration plus correcting the K deficit.
Chronic Complications of Diabetes Mellitus: Microvascular Disease In Diabetes Mellitus a thickening of the wall of small blood vessels causes ischemia & hypoxic damage to many tissues, especially nerves (causing neuropathy), the retina (causing retinopathy) & glomeruli of the kidneys (causing nephropathy). Diabetic Neuropathy damages neurons & Schwann cells causing demyelinisation of somatic & autonomic nerves thus slowing conduction. - causes decreased sensation & motor control in lower extremities so increased risk of injury & infections (due to a poorer immune response) leading to gangrene & foot amputations. - causes foot ulcers (most common diabetic hospitalisation). - decreased autonomic responses, e.g. vasomotor, cardiac, GI & urinary tract responses & erectile dysfunction in males. Diabetic Nephropathy in kidneys is leading cause of end stage renal disease (40% of kidney failures result from DM). Diabetic Retinopathy is the leading cause of acquired blindness.
Chronic Complications of Diabetes: Macrovascular Disease Type 2 Diabetes Mellitus is a major risk factor for Atherosclerosis which causes: Coronary Artery Disease (causing angina & heart attacks) Cerebrovascular Disease (causing strokes) Peripheral Vascular Disease of arteries to the lower extremities, causing calf pain, muscle atrophy, ulceration, necrosis & gangrene especially in the feet leading to amputation. 70% of diabetics die from cardiovascular disease!
Gestational Diabetes: Gestational (Type 4) Diabetes Mellitus is DM that occurs during pregnancy especially in women who - are obese - have had several pregnancies - have had a previously large (>9lb) baby - have family history of diabetes - are older Gestational DM is harmful to the fetus, causing excess RBCs, excess plasma Ca & bilirubin & hypoglycemia with an increased risk of congenital abnormalities & stillbirths. A large baby size causes complications at delivery. Treatment of GDM consists of diet management & administering Insulin. All pregnant women should have a risk assessment for GDM. A women with GDM has an increased risk for getting type 2 DM for years after pregnancy