2Learning Objectives Describe the origin & functions of insulin. Describe the following antagonistic hormones to insulin.Glucagon, Growth Hormone, Glucocorticoids (Cortisol), Catecholamines (Epinephrine).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.Describe the causes, manifestations, pathogenesis, treatment and complications of DM type 2.Describe the causes, manifestations, pathogenesis, treatment and complications of Gestational DM.References: Porth, Essentials, Ch. 17 Ch. 32Porth, Pathophysiology, Ch. 43
3Diabetes MellitusDiabetes 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.(apple shape bad:pear shape good)
4Origin & 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.Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin
5Functions of Insulin glucose uptake glycogenesis lipogenesis Skeletal muscleAdipose tissueProtein synthesisglucose uptake to form glycerolAmino acid uptakeglucose uptakewhen sufficient glycogen storedWhen the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells. Reference for this?glycogenesisFunctions of InsulinModified from Porth Essentials Figure 32-1Liver
6Structure 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 is secreted with insulin & is used to study B cell activityC peptideproinsulinPorth Essentials Fig 32-3Porth, Pathophysiology, fig 43-3
7Endocrine Pancreas: Islets of Langerhans glucagoninsulinamylinAmylin aids insulin byeffectively slowing the intestinal absorption of glucose &suppressing glucagon.Porth Essentials Figure 32-2Porth, Pathophysiology, fig 43-2
8Insulin Receptors on Target Cells Insulin binds to membrane receptors of target cellInsulin activates glucose transportersInsulin receptorInsulin activates enzymes for anabolic pathwaysInsulin activates amino acid carriersPorth Essentials Figure 32-5Porth, Pathophysiology, fig 43-6
9Antagonistic Hormones to Insulin Insulin is the only Hypoglycemic Hormone.Hyperglycemic Hormones are antagonistic 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.Prolonged excessive secretion or use of Glucocorticoids or Growth Hormone can cause Diabetes Mellitus.
10Diabetes Mellitus There are 4 types of Diabetes Mellitus DM is a group of metabolic diseases characterized by hyperglycemiaDM results from defects in insulin secretion, insulin action, or both.There are 4 types of Diabetes MellitusType 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.Porth HC table 43-2 orType 3 includes glucokinase deficiency in Beta cells
11Type 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.
12Type 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.Note nausea & vomiting from DKARef. Bullock & Henze, p. 699 (cramps, nausea, vomiting)Corwin, p (anorexia, nausea, vomiting for metabolic acidosis in general).Nowak & Hanford, p. 439 (ketone bodies in DKA can produce nausea & vomiting, are toxic to the brain & are volatile so detected on breath).Normal plasma glucose =100mg/dL= 1g/L/180 x 1000 = 5.55mmoles/L = 0.55 mmoles/dL
13Diagnosis of Diabetes Mellitus: Blood Glucose Tests Diagnosis of Diabetes Mellitus requires Plasma Glucose Testing.Normal fasting plasma glucose < 100mg/dL (5.55 mmol/LFasting Plasma Glucose is the preferred diagnostic test.FPG of >126 mg/dL (7 mmol/L) indicates DMCasual Plasma Glucose of >200mg/dL (11.1 mmol/L) indicates DMOral 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 DMGlycated Hemoglobin (Hb)Test- Glucose enters erythrocytes & combines with Hb- The higher the blood [glucose] the greater the % ofglycated (glycosylated) Hb (A1C): normal A1C < 6%: DM A1C >7%Normal plasma glucose =100mg/dL= 1g/L/180 x 1000 = 5.55mmoles/L = 0.55 mmoles/dL
14Ketoacidosis: Acute Complication of Type I Diabetes Mellitus 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.
15Diabetic Ketoacidosis (DKA): Manifestations Ketoacidosis is a form of Metabolic acidosisLow plama pH (< 7.3)Hyperventilation - increased BR & depth = Kussmaul’s respiration (respiratory compensation for metabolic acidosis).Low plasma bicarbonate (HCO3-) < 25 mEq/dL due to buffering of plasma by bicarbonate.KetonemiaKetonuriaFruity breath (due to acetone).Lethargy, nausea, vomiting & abdominal pain (note: vomiting compounds the dehydration already present).HyperglycemiaDepression of CNS causes stupor & eventual coma.
17Type 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.Exam q autoantibody testing would diagnose type ______ DM
18Type 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.
19An Acute Complication of Type I Diabetes Mellitus Hypoglycemia:An Acute Complication of Type I Diabetes MellitusHypoglycemia 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 alcoholSymptoms show rapid onset, are progressive & are due to- effects of hypoglycemia on CNS- compensatory activation of sympathetic NS.
20Hypoglycemia: Manifestations Effect of Hypoglycemia on CNSShakiness - Dizziness - Hunger - HeadacheSudden moodiness or behavior changesClumsy or jerky movementsDifficulty paying attention, or mental confusion- Tingling sensations around the mouth (paresthesia)- Anxiety - Seizures - comaCompensatory Activation of Sympathetic NSPale cool, clammy skinSweatingTachycardia
21Type 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 %).(apple shape bad:pear shape good)
22Type 2 Diabetes Mellitus: Risk Factors 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 contentBMI = 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).(apple shape bad:pear shape good)e.g. womanht 1.6mwt 50kgBMI = ?Answer: 19.53normale.g. womanht 1.6 wt 50kgBMI = ?Answer: 19.53normale.g. woman ht 1.6: wt 50kg BMI = ?Answer: 19.53normal
23Type 2 Diabetes Mellitus: Causes of Metabolic Abnormalities Major metabolic abnormalities in DM 2 are probably caused by:Genetic PredispositionIncreased levels of circulating Free Fatty Acids (FFAs) from diet or from lipolysis in enlarged adipocytes in obese persons.High levels of FFAs have 3 harmful effects:Peripheral Insulin ResistanceFFAs 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.
24Type 2 Diabetes Mellitus: Pathogenesis Environmental Risk FactorsGenetic predispositionFFAs cause cell failureinsulin resistanceObesityderanged insulin secretionFFAs cause peripheral insulin resistanceFFAs reduce hepatic response to insulinHyperglycemiaFrom Porth Essentials Figure 32-7Porth, Pathophysiology fig 43-7 hepatic glucose output (gluconeogenesis)Diabetes Type 2
25Type 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.Obesity rather than wt loss is present:ketosis is not common as some insulin is present so less reliance on fatty acids for energy than DM1.
26Type 2 Diabetes Mellitus vs Type 1 Diabetes Unlike Type 1 DMIn 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.Obesity rather than wt loss is present:ketosis is not common as some insulin is present so less reliance on fatty acids for energy than DM1.
27Treatment of Type 2 Diabetes Diet ManagementWeight LossExerciseOral 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 (a glucosidase inhibitors).- Increase insulin sensitivity of insulin dependent target tissues (adipose, muscle, liver) for Type 2 DM , e.g. TZDs.TZDs = THIAZOLINEDIONES
28Actions of Antidiabetic Drugs in Type 2 DM Drug stimulates beta cells to secrete more insulinDrug delays absorption of glucoseDrugs prevent hyperglycemiaFrom Porth Essentials Figure 32-8APorth, Pathophysiology fig 43-8ADrugs prevent hyperglycemiaDrug increases insulin dependent glucose uptake of target cells.Drug reduces glucose output by liver
29Manifestations include Acute Complication of Type 2 Diabetes Mellitus: Hyperglycemic Hyperosmolar StateHHS 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.Microvascular disorders are in insulin independent tissues so high ICF levels of glucose occur.60- 70% of patients with foot ulcers do not have CV disease, just neuropathy causing lack of pain sensation.Microvascular disease chracterised by thickening & increased collagen in basement membranes of small vessels.Neuropathy due to combination of factors, ischemia, hyperosmolarity etc. (Bullock, 704)
30Chronic 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.Microvascular disorders are in insulin independent tissues so high ICF levels of glucose occur.60- 70% of patients with foot ulcers do not have CV disease, just neuropathy causing lack of pain sensation.Microvascular disease chracterised by thickening & increased collagen in basement membranes of small vessels.Neuropathy due to combination of factors, ischemia, hyperosmolarity etc. (Bullock, 704)
31Chronic 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.Microvascular disorders are in insulin independent tissues so high ICF levels of glucose occur.60- 70% of patients with foot ulcers do not have CV disease, just neuropathy causing lack of pain sensation.Microvascular disease chracterised by thickening & increased collagen in basement membranes of small vessels.Neuropathy due to combination of factors, ischemia, hyperosmolarity etc. (Bullock, 704)70% of diabetics die from cardiovascular disease!
32Gestational 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 olderGestational 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.Microvascular disorders are in insulin independent tissues so high ICF levels of glucose occur.60- 70% of patients with foot ulcers do not have CV disease, just neuropathy causing lack of pain sensation.Microvascular disease chracterised by thickening & increased collagen in basement membranes of small vessels.Neuropathy due to combination of factors, ischemia, hyperosmolarity etc. (Bullock, 704)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