Diabetes Mellitus & Its Tests PDF - University of Gharyan

Diabetes Mellitus & Its Tests Dr. Kamal A. A  Learning objectives To understand: ✓ The biochemical basis of diabetes, the most common metabolic disorder, whose incidence is increasing. ✓ The biochemical events & measurements that are particularly important in: ...

Diabetes Mellitus & Its Tests Dr. Kamal A. A  Learning objectives To understand: ✓ The biochemical basis of diabetes, the most common metabolic disorder, whose incidence is increasing. ✓ The biochemical events & measurements that are particularly important in:  Classification & Causes  Diagnosis  Monitoring, Control and Treatment  Complications  Terminology  Hyperglycemia: High blood sugar blood.  Gestational diabetes: diabetes in pregnant women.  Homeostasis: A state of balance among all the body systems.  HLA-DR3 and HLA-DR4: human leukocyte antigen.  Microbiome: community of microorganism lives in such place as in human body.  Hemoglobinopathies: disease involve red blood cells.  Neuropathy: central nervous system disease.  Retinopathy: disease of the eye.  Nephropathy :diseases involve kidneys.  Ketosis: refer to ketone bodies fatty acids oxidation  Diabetes Mellitus  Diabetes mellitus is a metabolic disorder in which the body’s ability to produce or respond to insulin is impaired, resulting in high blood glucose level.  The medical term for high blood glucose levels is hyperglycemia.  Diabetes is a Greek word means to pass through, and mellitus” is Latin word means sweet.  Diabetes mellitus can be classified into 3 main types: a. Type 1 Diabetes Mellitus b. Type 2 Diabetes Mellitus  Other types of diabetes  Maturity onset diabetes of the young (MODY)  Neonatal diabetes.  Wolfram Syndrome.  Alström Syndrome.  Latent Autoimmune diabetes in Adults (LADA)  Postprandial response to High glucose  Regulation of glucose needs two separate signals: The first signal from high glucose to pancreas To stimulate insulin secretion from pancreas The second signal from insulin to the target cells In muscle, adipose tissue and liver to permit glucose in and to utilize glucose  This is effectively lowers blood glucose  Glucose homeostasis The proper glucose homeostasis requires:  Actions of several organ including but not limited to, the brain, liver, skeletal muscle, and adipose tissue.  Specific set of metabolic hormones such as hormones released from the pancreas, gut hormones, and hormones produced by adipose tissue  Glucose transporters are a wide group of membrane protein facilitate the transport of glucose across the plasma membrane by facilitated diffusion What are the main type of glucose transporters  Overview of Insulin Function INSULIN MUSCLE LIVER ADIPOCYTE Transports Forms inhibits glucose glucose, triglycerides production; allows amino acids glycogen storage to store fat; and ions inhibits lipolysis )K &phos( Overview of Insulin Function  Type 1 diabetes  Autoimmune destruction of insulin producing cells of pancreas (beta cells).  As a result no insulin so no glucose uptake by tissues and consequently blood glucose levels will be increased.  Mostly develops in younger (peak age of approximately 13 years old) but adults can also develop the disease.  Less common than type 2 diabetes only 8% of diabetes diagnoses  ?What Causes Type 1 Diabetes The cause of type 1 diabetes development is not yet known (just theories):  Viral theory: Say type 1 diabetes could be triggered by infections such as coxsackie virus.  Autoantibodies theory: Another theory links type 1 diabetes to autoantibodies against beta cell antigens  Genetics theory: There may also be a genetic link, with a strong association between type 1 diabetes and the presence of HLA-DR3 and HLA-DR4 antigens on chromosome 6  Risk Factors for Type 1 Diabetes  Family History of diabetes & other autoimmune diseases  Environmental Factors: (Obesity, microbiome)  Diet: such as: Early introduction of cereal in early life (prior to 3 months of age) Lack of vitamin D exposure More in northern climates than in southern. Higher in winter than in in summer months  Diagnosis (Tests of Type 1 DM)  Fasting Blood Sugar Test A fasting blood sugar test (also known as fasting plasma glucose, FPG) is a blood test that checks the blood sugar levels after not consumed any food or drink (except water) for at least 8 hours prior to the test.  Random Blood Sugar Test Random blood glucose (RBG) checking regardless of when the last meal was. Blood glucose level of 200 mg/dL (11.1 mmol/L) or higher could be suggestive of diabetes. Con: Diagnosis (Tests of Type 1 DM)  Hemoglobin A1C Test (HbA1c): It measures sugar over the past 2-3 months (8-12 weeks) so it is the best test for follow up. HbA1c does not require the patient to be fasted HbA1c affected by RBCs turnover so not suitable hemoglobinopathies, ongoing anemia or HIV. HbA1c also not recommended in pregnant (OGTT). STUDY TIP - Remember that although an  Other Tests of Type 1 Done if diabetes diagnosed by one of the methods above:  Urinalysis: to assess ketones and glucose in the urine  C-peptide: Differentiate between different types of diabetes, low in type 1 and high in type 2  Diabetes autoantibodies: such as glutamate decarboxylase , islet cell autoantibodies, and insulin autoantibodies especially if the presentation is atypical such in case of > 40 years & no family history of diabetes  Type 1 DM Treatment 1. Education  Patient education is an important part of managing type 1 diabetes.  Patients with type 1 diabetes must take insulin in proper (type, dose and time) way so glucose can be transported from blood into the cells.  Patients will be offered educational programs to allow self-management of their diabetes.  Annual reviews will also offer.  Con: Type 1 DM Treatment 2. Insulin:  Insulin therapy is the main treatment for type 1 Types of insulin (varying onset, peak, and duration). - Rapid-Acting: Insulin aspart , nsulin lispro - Short-Acting: human regular (Humulin R) - Intermediate-Acting: NPH (Humulin N) - Long-Acting: detemir (Levemir), glargine (Lantus) - Ultra-Long Acting: glargine U-300  Type 1 DM Medication  Start with basal- bolus, this involve multiple daily injections of a rapid or short acting insulin before meals, and an intermediate or long acting injection once or twice daily.  A combination of different types to mimic the normal physiological insulin.  Routes; SC in Abdomen, Outer Thigh, Back of the Upper Arm, Hip and Upper Buttocks.  Annually review diabetic history screening, how managing goes, Eye checking, Urinalysis and BMI to assess cardiovascular risk.  Sick Day Rules Stress, such as acute illness, increase cortisol production and this increase blood glucose levels meals.  Type 2 diabetes  When response to insulin is reduced (insulin resistance).  Insulin production initially increased to counteract the resistance.  However, over time there progressive decrease in production & secretion causing insufficient insulin levels.  The combination of the resistance and impaired of secretion results in type 2 diabetes.  More common than type 1 diabetes (90%)  Usually develops in obese and mostly in older (over 45 years old) with a peak incidence of diagnosis at 60 years.  However, the incidence has increased in children and adolescents due to rising obesity levels, physical inactivity, etc.  ?What Causes Type 2 Diabetes  Type 2 diabetes develops when the pancreatic beta cells secrete less insulin than the body requires (insufficient insulin), or the cells in the body stop responding to insulin (insulin resistance).  In other words, type 2 diabetes is an insulin-resistant condition with associated pancreatic beta cell dysfunction. :Insulin resistance can be caused by  Metabolic Syndrome (3 or more of the following High blood glucose Low levels of HDL (good) cholesterol High levels of triglycerides Large waist circumference High blood pressure  Obesity - Adipose tissue promotes insulin resistance through inflammatory mechanisms Lack of exercise Poor diet  Genetics - Abnormal gene functioning can lead to insulin resistance and/or pancreatic beta cell dysfunction  Pathophysiology of type 2  For type 2 both insulin resistance and inadequate insulin secretion must be present.  Glucose cannot be taken up into the cell from blood.  Blood is full of sugar (glucose; the nutrient) but the sugar cannot enter the cells due to reduced insulin action and eventual overall lack of insulin (polyphagia).  Body try to increase insulin production and secretion to fix to overcome the lack of sensitivity of insulin and allow the body’s cells to take up glucose.  However this effort eventually lead to accelerated beta cell changes and/or damage.  This will cause a subsequent decrease in insulin production and secretion and patient will begin to experience symptoms of diabetes.  Tests of type 2 DM a. Random blood sugar test b. Fasting blood sugar test c. Oral glucose tolerance test d. Hemoglobin A1C  Patients with symptoms of diabetes may only require 1 biochemical test to confirm the diagnosis of type 2.  However, patients with no symptoms typically require 2 separate investigations on different occasions.  Both tests must have results which confirm the diagnosis.  Prediabetes = Blood sugar levels are higher  Oral glucose tolerance  tests (OGTT) Done to measure how well the body can process larger amounts of sugar, there are two types of OGTT:  Glucose challenge test The test can be done at any time of the day. Involves drinking 50 (g) of glucose in 250 -300 ml water. After one hour has passed blood sugar level checked.  Glucose tolerance test Involve over night fasting (only water) First of all determine your baseline blood sugar level. Then drink a glass of sugar solution (75g in 250- 300ml) If the test for confirmation of diabetes, blood is drawn again after two hours and sugar level is measured. In gestational diabetes, blood checked hour after  Treatment of type 2 DM  Oral Diabetes Medications – (Hypoglycemic Agents) Routinely used before insulin for the treatment of type 2 diabetes. Examples of oral diabetes medications include: Biguanides (metformin) Thiazolidinediones (pioglitazone, rosiglitazone) Sulfonylureas (glimepiride, glyburide, glipizide) SGLT-2 Inhibitors (dapagliflozin, canagliflozin, empagliflozin) DPP-4 Inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin) Con: Medication of type2 DM  Insulin therapy: If diet, exercise, lifestyle modifications, and oral antidiabetes medications are not effective In some instances, insulin may be recommended first as an initial treatment. When given insulin, patients with type 2 diabetes typically continue their oral diabetes medication, but use an intermediate-acting or long-acting insulin (“basal” insulin) at bedtime or twice daily.  Biochemical basis of some antidiabetic drugs action  Biguanides: Act on and block enzyme regulates the balance in metabolism they activate fatty acid oxidation and decrease glycogenolysis & gluconeogenesis so glucose delivery from the liver decreased.  Sulfonylureas: Bind to and close the ATP-sensitive K channel stop the efflux of K causing depolarization which leads to insulin release  α-glucosidase inhibitors: Inhibit α-glucosidase enzymes (sucrase, maltase, dextranase) which decrease intestinal absorption of complex carbohydrates.  Thiazolidinediones: bind receptor act in synthesis and activation of proteins involved in glucose uptake & process so increase insulin-sensitivity (adipocytes).  Pathophysiology of diabetes complications  Cardiovascular effect: due to endothelial, vascular smooth muscle cell, and platelet functions abnormalities associated with atherosclerotic plaque in the vasculature supplying the heart, brain, limbs, and other organs.  Neuropathy, foot ulcers: involve vascular, and immune system beside hyperglycemia produces oxidative stress on nerve cells and leads to neuropathy.  Retinopathy? Free radicals and glycosylated protein damage and increased vascular  Diabetic ketoacidosis  It may be the presenting picture in patient not recognized as diabetic  In known diabetes, it may be precipitated by omitting insulin doses, or by inadequate insulin dose.  The clinical features are dehydration, ketosis and hyperventilation (‘air hunger’).  Insulin deficiency, accompanied by raised counter-regulatory hormones (adrenaline, cortisol, GH and glucagon).  Hyperglycaemia causes extracellular hyperosmolality result in intracellular dehydration as well as to an osmotic diuresis.  The osmotic diuresis causes loss of water, Na+, K+, calcium and other inorganic constituents, and leads to a fall in circulating blood volume.  No insulin more lipolysis more fatty acid oxidation and so more ketone bodies (ketosis).  Ketone bodies stimulate the chemoreceptor trigger zone, so vomiting may exacerbate all these effects.  The increased production of ketone bodies causes a metabolic acidosis with associated hyperkalaemia. Consideration when managing Diabetes  Metformin : Start by low dose to prevent GIT irritation then gradually increased till HbA1c begin to decrease.  The target A1C for monotherapy cases on metformin is ≤ 6.5%.  If target glucose levels not achieved on metformin, a 2nd oral medication may be added.  If the initial HbA1c is ≥ 7.5% start metformin & another second-line oral medication immediately.  Consider SGLT-2 inhibitors or GLP-1 agonists cardiovascular disease or chronic heart failure (or is at risk of to reduce cardiovascular morbidity and mortality.  Pioglitazone shown to increase the risk of bladder cancer, so not given to patient with UB risk.  Also Pioglitazone contraindicated in heart failure..  Summary: Type 1DM Pathogenesis: Autoimmune destruction of β cells in genetically susceptible individuals causing a severe deficiency of insulin Risk factors: Factors that trigger the autoimmune response. Infection with mumps virus, coxsackie B virus Rotavirus or EBV. Associated with HLA- DR3-DQ2, HLA- DR4-DQ8 genes or both Clinical presentation: Polyuria, Polydipsia, Polyphagia, Weight loss, Blurred vision, Fungal infections , Numbness, tingling of hands & feet Diagnosis: 1. FPG) (Specific) 2. HbA1c 3. RBG (Sensitive) 4. OGTT Management: Summary: Type 2DM Pathogenesis: Due to insulin resistance and an inability to produce sufficient insulin to overcome this ‘insulin resistance’. Risk factor Obesity Sedentary lifestyle Metabolic syndrome Impaired glucose tolerance Impaired fasting glucose Clinical presentation: Polyuria , Polydipsia , Weight loss, Blurred vision Fungal infections , Numbness, tingling of hands and feet Diagnosis: 1. FPG (Specific) 2. RBG (Sensitive) 3. (OGTT) (Sensitive & Specific) 4. (HbA1c) Management Diet and lifestyle changes 3 options are metformin, a sulfonylurea or a thiazolidinedione. If control is inadequate on oral therapy, insulin therapy should be started without undue delay  Lecture Quiz: CASE 1  A 27-year-old man was referred to the local diabetes clinic. He had been diagnosed as having type 2 diabetes 3 years previously and his control was poor (HbA1c 9.6%) despite being on good doses of metformin.. Several close family members also had diabetes, he was slightly overweight with a BMI of 26, and he was normotensive. The GP was wondering whether he needed to start on insulin.  What is your comment regarding the diagnosis and line of management?. Lecture Quiz: CASE 2 14-year-old boy drowsy and uncooperative state. When the GP arrived they told her that he seemed to be unusually thirsty for the last 1–2 months with weight loss. Recently, he complaining of abdominal pain and discomfort. O/E he was semi-conscious, with deep sighing respiration, PR (120/min), BP 94/56 with cold extremities. Chemical investigations shows: ↑Urea 24.5 mmol/L - ↓Na+ 128 mmol/L - ↑ K+ 6.9 - ↑ Glucose 35.2 mmol/L - ↑ H+ 82 nmol/L – ↓ PCO2 2.9 kPa - ↓ HCO− 3 7.0 mmol/L - PO2 14.0 kPa What is the probable diagnosis, and how be confirm this quickly? What principles guide of the treatment of this patient? What is the biochemical basis regarding the events of the case? Thanks for your atention Author : Dr. KAMAL A A