Diagnosing Diabetes Mellitus PDF

# Diagnosing Diabetes Mellitus ## Presenter - Dr Verena Gounden - Consultant Chemical Pathologist - Galway University Hospitals ## Diabetes Mellitus - A group of disorders of abnormal carbohydrate metabolism characterized by hyperglycaemia. - Relative or absolute impairment of insulin secretion...

# Diagnosing Diabetes Mellitus ## Presenter - Dr Verena Gounden - Consultant Chemical Pathologist - Galway University Hospitals ## Diabetes Mellitus - A group of disorders of abnormal carbohydrate metabolism characterized by hyperglycaemia. - Relative or absolute impairment of insulin secretion by the islet cells of the pancreas, along with varying degrees of peripheral resistance to the action of insulin. ## Normal Carbohydrate Metabolism - Blood glucose levels are normally maintained within a relatively narrow range (4-8 mmol/L). - This ensures glucose is available as: - an energy source (oxidized to $H_2O$ and $CO_2$ yielding energy in the form of ATP) - a precursor to complex carbohydrates, proteins and lipids - On eating: - Complex carbohydrates are hydrolysed to simple sugars (including glucose, fructose and galactose) that are absorbed through the small intestine into the bloodstream. - The rise in blood glucose stimulates insulin release from the pancreas. - Insulin stimulates tissues to use the excess blood glucose: - Activating glucose uptake into muscle and adipose tissue. - Activating glycogen synthesis and inhibiting glycogenolysis in muscle and liver cells. - Inhibiting gluconeogenesis - Blood glucose levels fall. - Between meals: - As blood glucose levels fall, insulin secretion by the pancreas slows and glucagon is released. - Gluconeogenesis and glycogenolysis are activated to maintain blood glucose levels. - In prolonged fasting: - Lipids become an increasingly important energy source. - Fatty acids are released from adipose tissue (lipolysis) and these can be used as an energy source by a variety of tissues (β-oxidation). - Fatty acids cannot cross the blood brain barrier. When blood glucose levels are low, liver cells partially metabolise fatty acids releasing ketone bodies into the bloodstream. Ketone bodies can cross the blood brain barrier and can be taken up by brain cells as an energy source. ## A Diagram Depicting Normal Carbohydrate Metabolism - Shows the blood glucose levels in mmol/L and serum insulin in pmol/L over a 24-hour period. - The graph starts at 7:00 am and ends at 7:00 am the next day. - There are three lines on the graph, representing glucose blood levels, insulin blood levels, starch-rich food, and sucrose-rich food. - There are labels for breakfast, lunch and dinner indicated on the x-axis. ## Normal Carbohydrate Metabolism: Role of Insulin - **Liver**: Insulin helps promote the transport of glucose from the blood into hepatocytes, where it is further converted to glycogen, fatty acids, and triglycerides. - **Skeletal muscles**: Facilitates the uptake of glucose and amino acids from the bloodstream. - Amino acids are subsequently used for functional protein synthesis. - Glucose is mostly utilized in glycolysis to produce energy in the form of ATP. - Glucose may also be converted to glycogen. - **Insulin stimulates adipose tissue uptake** of fatty acids, which are later converted into triglycerides and used as long-term energy stores. - **Without insulin**, the following occurs: - Glucose is not taken up by muscle and adipose tissue. - Glycogenolysis is activated in liver and muscle. - Proteins are catabolized for energy and gluconeogenesis (not confirmed - uncertain about this). - Blood glucose levels rise. - Fatty acids are released into the bloodstream, used as an energy source, triglycerides are resynthesized in the liver, and repackaged into lipoproteins. - Fatty acids are partially metabolized to ketone bodies that can be taken up as an energy source by brain cells. ## Normal Carbohydrate Metabolism: Role of Incretin Hormones - Gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. - Examples: - GIP (glucose-dependent insulinotropic polypeptide) - GLP-1 (glucagon-like peptide-1) - Incretin effect describes the phenomenon that oral glucose, absorbed from the gut, leads to the stimulated secretion of both GIP and GLP-1, which in turn provides a stimulus to β-cells to augment their insulin secretory responses, while intravenous glucose does not raise plasma concentrations of either GIP or GLP-1. - Multiple effects on various organ systems - relevant is a reduction in appetite and food intake. ## DM Classification - **Type 1 diabetes** - **Type 2 diabetes** - **Gestational diabetes** - **Genetic defects of the beta-cell** - **Hybrid forms of diabetes** - Slowly evolving immune-mediated diabetes (autoimmune - LADA) - Ketosis-prone type 2 diabetes - **Infections** - **Genetic defects in insulin action** - **Uncommon forms of immune-mediated diabetes** - **Endocrinopathies** - **Other genetic syndromes** - Other genetic syndromes are sometimes associated with diabetes. - **Other Special types of DM** - **Diseases of the exocrine pancreas** - **Drug- or chemical-induced diabetes** ### DM Classification Description - **Type 1 Diabetes Mellitus** - In Ireland - ~15,000 cases. - **Type 2 Diabetes Mellitus** - In Ireland - ~210,000 cases. - **Maturity Onset Diabetes of the Young (MODY)** - 2 to 5 percent of diabetes. - Non-insulin dependent diabetes diagnosed at a young age (<25 years) with autosomal dominant transmission and lack of auto-antibodies. - Many patients are misclassified as having either type 1 or 2 diabetes. - **Diseases of the pancreas** - Cystic fibrosis, hereditary hemochromatosis, chronic pancreatitis. - **Endocrinopathies** - Cushing syndrome and acromegaly can lead to glucose dysregulation. - **Drug-induced diabetes** - A variety of drugs can impair glucose tolerance including corticosteroids, antipsychotics, immunosuppressants. - **Gestational Diabetes Mellitus** - ~12.4% of women develop a form of diabetes in pregnancy (Atlantic DIP 2012). - Increased risk of several adverse outcomes in pregnancy: - Pre-eclampsia, hydramnios, macrosomia, perinatal mortality, miscarriage, etc. - Usually resolves post-partum but mothers at increased risk of developing type 2 DM. ## Symptoms Associated with Hyperglycaemia and Glycosuria - **Polyuria** - Filtered glucose exceeds tubular reabsorption threshold. - Osmotic diuresis created by glucose in urine. - **Polydipsia** - Combination of hyperglycaemia and water loss in urine result in plasma hyperosmolality. - Hypertonicity is detected by specialised hypothalamic cells (osmoreceptors). These osmoreceptors, along with angiotensin II, released secondary to volume depletion, stimulate thirst centres. - **Weight loss** - Glycosuria and excess utilization of fat and protein as energy source. - **Fatigue and hunger** - Inability of blood glucose to enter cells for glycolysis. ## Diabetes Prevalence - **Diabetes around the world in 2021**: Approximately 537 million adults (20-79 years) are living with diabetes. - **643 million by 2030**: The total number of people living with diabetes is projected to rise to 643 million by 2030 and 783 million by 2045. - **3 in 4**: 3 in 4 adults with diabetes live in low- and middle-income countries. ## A Map Showing Diabetes Prevalence Around the World - Shows a world map, highlighting the number of people living with diabetes by region in 2025, 2030 and 2045. - Each region is color-coded and shows the percentage increase in diabetes prevalence by 2045. ## Trend in Prevalence of Diabetes - A graph depicting the prevalence of diabetes from 1980 to 2014. - The x-axis of the graph shows the year, while the y-axis shows the prevalence of diabetes. - The graph shows the prevalence of diabetes in low-income, lower middle-income, upper middle-income, high-income regions, and the world. ## Diagnosing Diabetes Mellitus - Diagnosing diabetes mellitus is based on demonstrating hyperglycaemia through: - **Diabetes symptoms** (polyuria, polydipsia and unexplained weight loss) plus: - a random venous plasma glucose concentration > 11.1 mmol/L - a fasting plasma glucose concentration > 7.0 mmol/L - plasma glucose concentration > 11.1 mmol/L two hours after 75g anhydrous glucose in an oral glucose tolerance test (OGTT). - **With no symptoms**: diagnosis requires elevated glucose levels on at least two occasions. - **An HbA1c of >48 mmol/mol**. - Note: None of these tests are specific for type of diabetes. Type is usually established based on clinical presentation. ## Plasma Glucose - Plasma is blood minus the cellular constituents (e.g. red blood cells, white blood cells and platelets). - Important pre-analytical issues in ensuring accurate plasma glucose levels: - **Clarity on patient state** (Fasting, 2 hour post glucose load, random): - Critical to document time and fasting state of patient for accurate interpretation. - **Specimen tube must prevent blood clotting**: - If a clot forms, more difficult to get a clean separation of the cells from the plasma. - Tubes with oxalate salts prevent clotting by forming insoluble complexes with the calcium in the blood which is required for clotting. - **Specimen tube must prevent glycolysis**: - Blood cells will continue to metabolise glucose in vitro. - Sodium fluoride to inhibit enzymes involved in glycolysis. - New tubes in UHG with citrate buffer to get more immediate enzyme block and more accurate results. ## Hb A1c - Proteins are continuously undergoing non-enzymatic chemically modification by glucose (glycation). - Results in advanced glycation products (AGE) which may contribute to microvascular and macrovascular complications of diabetes. - Hb A1c is formed by the glycation of the N-terminal valine residue of each β-chain of Hb A with glucose. - Formation of Hb A1c is essentially irreversible. - The concentration in the blood depends on the lifespan of the red blood cell (average 120 days) and the blood glucose concentration. - It therefore reflects the integrated value for blood glucose over the preceding 6-8 weeks. ## A Diagram Showing Normal Hb A1c - Depicts an A1c Haemoglobin Electrophoresis diagram, along with the fractions, percentage, mmol/mol and calculated percentage. ## Hb A1c in Diagnosis - DCCT units for Hb A1c were given as a % of Hb that is glycated. - We now use IFCC units (mmol of Hb A1c per mol of Hb A). - Hb A1c has been accepted as a diagnostic indicator of diabetes mellitus at >48 mmol/mol. ## Raised HbA1c - Depicts an A1c Haemoglobin Electrophoresis diagram, highlighting a raised Hb A1c along with the fractions, percentage, mmol/mol and calculated percentage. ## Hb A1c in Diagnosis - Caution required with interpretation because of: - **Shortened RBC lifespan**: This could result in a ↓ Hb A1c. - Haemolytic disease - Recent significant blood loss - **Increased lifespan**: This results in ↑ HbA1c. - Iron deficiency anaemia. - **Haemoglobin variants**: This can interfere with RBC lifespan, Hb glycation and analytical methods. - Hb S, Hb F, Hb C ## Hb Electrophoresis in Sickle Cell Trait - Depicts a Hb Electrophoresis diagram, highlighting an atypical profile with Hb A1c, other Hb A, Hb A0, Hb S, Hb A2 fractions. - It also shows a table with fractions, percentage mmol/mol and calculated percentage. ## Gestational Diabetes - Woman without diabetes may become hyperglycaemic during pregnancy. - Associate with increased risk of: - pre-eclampsia - requiring a Caesarean section - large babies at risk of complications during labour, such as shoulder dystocia - neonatal hypoglycaemia - stillbirth - children being overweight and developing type 2 diabetes. - **Maternal risk factors**: - being overweight - previously having gestational diabetes - a family history of type 2 diabetes - having polycystic ovarian syndrome. ## GDM Screening | Feature | One-step | Two-step | |---|---|---| | Fact | More women are diagnosed GDM (2- to 3-fold compared to the two-step approach). | Less women are diagnosed with GDM. | | Strength | Using a 75 g OGTT as in the nonpregnant state. GDM screening test can be done at a single visit. Based on a large-scale, multinational study assessing adverse pregnancy outcomes (HAPO study). May prevent long-term maternal and offspring complications by including milder forms of GDM (but no differences were found for adverse pregnancy outcomes from the two RCTs). | Easier screening (a 50 g GCT), which does not require fasting. Less socioeconomic burden. | | Weakness | All pregnant women need fasting ≥ 8 hours and undergo a 2-hour OGTT. More women may suffer from mental stress having been diagnosed and treated for GDM. Higher socioeconomic burden. | ~20% of women should return for a 3-hour OGTT with fasting ≥ 8 hours. | - In Galway, at-risk women are screened using an oral glucose tolerance test at 24-28 weeks gestation. ## Diabetes Risk States - **Impaired Fasting Glycaemia/Glucose** - Fasting glucose 5.6-7.0 mmol/l. - Suggests hepatic insulin resistance. - Associated with a markedly increased risk of developing type II diabetes mellitus. - **Impaired Glucose Tolerance** - OGTT 2h glucose 7.8-11.0 mmol/l. - Suggests muscle insulin resistance. - Associated with a small increased risk of microvascular disease and a substantially increased risk of macrovascular disease. - As HbA1c climbs from 34 to 48 mmol/l the 5 year risk of T2DM increases markedly. ## T1DM Clinical Presentation - Peak age is around puberty, but it may present at any age. - The most common presentation is with clinical features associated with hyperglycaemia: - Polyuria, polydipsia, fatigue, hunger, weight loss, blurred vision. - DKA. - **Timeframe**: - Days, weeks or months. - Shorter in children, more insidious in adults. - **Infection commonly precipitates the initial presentation**: - Fever, sore throat, cough, dysuria. - In practice, at diagnosis, patients with T1DM commonly have glucose levels of 15-30 mmol/L and about 25% present with diabetic ketoacidosis. ## Diabetes Associated Antibodies - Results from the autoimmune destruction of the insulin-producing beta cells in the pancreas. - Antibodies are often detectable to: - insulin - particularly in children - 65-kD isoform of glutamic acid decarboxylase (GAD 65) - particularly in adults. - islet cells. - Anti-Tyrosine phosphate like protein (IA2). - And-Zn transporter 8 (ZnT8). - The precise role for these antibodies in differentiating Type I and Type II has still to be elucidated. ## Determinants and Risk Factors for T2DM - **Genetics**: A significant contributory factor: - Family history - Ethnicity: Asians > Hispanics > Blacks > Whites - **Demographic characteristics**: - Risk increases with age. - Females at higher risk than males. - **Lifestyle**: - Obesity (central adiposity), physical inactivity, smoking. - Too much or too little sleep. - Red meat, processed meat and sugary drinks are associated with an increased risk. - Fruits, vegetables, nuts, whole grains, and olive oil are associated with a reduced risk. - Westernisation, urbanisation, modernization. - Traditionally a disorder of aging but the prevalence of obesity and T2DM in children is rising dramatically. ## Insulin Resistance - An impaired biological response to insulin found in T2DM. - The pancreas makes insulin but the tissues don't respond as well to it. - Reduced insulin-stimulated glucose transport and metabolism in adipocytes and skeletal muscle. - Impaired suppression of hepatic glucose output. - Insulin resistance is usually combined with some degree of β-cell dysfunction in T2DM. ## Type 2 Diabetes Mellitus (T2DM) - Pancreas ends up producing more insulin in order to get the same. - β-cell hyperplasia and hypertrophy helps maintain normal glucose levels. - Over time the pancreas becomes hypotrophic and hypoplastic and glucose levels rise. - Diabetic ketoacidosis usually doesn't develop as there is some insulin which limits lipolysis. ## 1 or 2? - No set criteria, but based on clinical presentation and history, sometimes supported by laboratory studies. - **Body habitus**: - Children with T1DM usually not obese and recent hx of weight loss. - T2DM usually, but not necessarily, obese. - **Age**: - T1DM usually present as children. - T2DM usually present later, but with obesity may present in childhood. - **Insulin resistance**: - T2DM frequently have acanthosis nigricans, hypertension, dyslipidemia, and polycystic ovary syndrome. - **Family history**: - 10% in T1DM. - Up to 75-90% in T2DM. ## 1 or 2? - **Laboratory tests**: - **Auto-antibodies**: An indicator of T1DM, but may be present in T2DM (?slowly progressive autoimmune disease). - **Higher fasting insulin and c-peptide levels**: Found in T2DM. - **MODY**: - Family History in keeping with autosomal dominant inheritance. - Genetic testing can be arranged.