Diabetes Mellitus and Glucose Regulation

Hormone Regulation of Blood Glucose

• Largely controlled by pancreatic endocrine hormones: glucagon and insulin.

• Achieved through a negative feedback loop that maintains glucose homeostasis.

Glucagon

• Secreted by pancreatic α-cells in response to low plasma glucose levels.

• Secretion increases with decreased plasma glucose, stimulating hepatic glycogenolysis (breakdown of glycogen to glucose) & gluconeogenesis (synthesis of glucose from non-carbohydrate sources).

• Glucagon also inhibits glycolysis to prevent the breakdown of newly synthesized glucose.

Insulin

• Secreted by pancreatic β-cells in response to increased plasma glucose.

• Facilitates glucose entry into muscles and adipose cells via insulin receptors, primarily through GLUT4 transporters.

• Stimulates glycolysis (glucose breakdown), glycogenesis (glycogen synthesis), and lipogenesis (fatty acid synthesis).

• Inhibits glycogenolysis and gluconeogenesis in the liver, promoting glucose storage and utilization.

Extracellular Glucose

• Important for brain cell function, as the brain relies almost exclusively on glucose for energy under normal conditions.

• Maintained between 4.5 to 11 mmol/L to ensure adequate glucose supply to tissues without causing hyperglycemic damage.

• Kidney reabsorbs glucose in the proximal tubules; glycosuria occurs when plasma glucose exceeds the renal threshold (>11 mmol/L), indicating saturation of glucose transporters in the kidneys.

Hypoglycaemia

• Blood glucose usually less than 3 mmol/L.

• Symptoms: pale, cold skin, rapid pulse, confusion, and in severe cases, loss of consciousness or seizures.

• Causes: Too much insulin (e.g., insulin overdose), not enough food intake, unexpected or excessive exercise, certain medications, or underlying medical conditions.

Hyperglycaemia

• Blood glucose usually greater than 20 mmol/L.

• Symptoms: flushed skin, thirst, frequent urination, sweet breath odor (due to ketone production).

• Causes: Insufficient insulin, excessive food intake (especially carbohydrates), infection, stress, or non-adherence to diabetes management plans.

• Long term effects: Stroke, Diabetic Retinopathy (damage to the blood vessels in the retina), Peripheral vascular diseases (narrowing of blood vessels reducing blood flow to limbs), and increased risk of infections.

Diabetes Mellitus Type 1

• Autoimmune destruction of pancreatic β-cells, leading to absolute insulin deficiency.

• Increased ketones, decreased insulin, increased glucagon, leading to increased gluconeogenesis and lipolysis, resulting in hyperglycemia and ketoacidosis.

• Requires exogenous insulin to prevent ketoacidosis and maintain glucose control.

Diabetes Mellitus Type 2

• Hyperglycaemia due to insulin resistance (cells do not respond effectively to insulin) and secretory defect (pancreas does not produce enough insulin).

• Less likely to have ketoacidosis due to the presence of some insulin, which prevents excessive lipolysis.

• Decreased fatty acid oxidation leads to increased triglycerides, contributing to dyslipidemia and cardiovascular risk.

Ketoacidosis (DKA)

• Life-threatening condition where the body breaks down fat too quickly, producing ketones, leading to metabolic acidosis.

• May occur in type 1 DM patients who miss insulin doses or have increased insulin requirements due to infection or illness.

Ketones

• Byproducts of fat metabolism, produced when glucose is not available as a primary energy source.

• Reflect intracellular glucose deficiency and low insulin activity, indicating reliance on fat metabolism for energy.

• Types: acetoacetate, beta-hydroxybutyrate, acetone; measured in blood or urine to assess the severity of ketosis.

Ketosis vs Ketoacidosis

• Ketosis: ketones 0.5-10 mmol, blood glucose 60-120. A normal metabolic state during fasting or low-carbohydrate diets.

• DKA: ketones >15 mmol, blood glucose >200. A severe metabolic state requiring immediate medical intervention.

Laboratory Investigations

• Blood samples: use sodium fluoride tubes to inhibit glycolysis and prevent artificial reduction of glucose levels.

• Urine samples: collect 1 hour post-meal; double void technique may be used to ensure the sample reflects current glucose excretion.

Oral Glucose Tolerance Test (OGTT)

• Fast overnight, administer 75g glucose in 300ml water, and measure plasma glucose levels at specific intervals (e.g., 0, 1, and 2 hours).

• Monitor glucose levels over time to assess the body's ability to handle a glucose load.

• Diabetic curve: high fasting glucose, delayed return to normal, indicating impaired glucose tolerance.

• Lag curve: rapid rise and fall, may indicate hyperthyroidism or early DM, reflecting rapid glucose absorption and metabolism.

Gestational Diabetes

• Diagnosed in pregnancy, usually between 22-24 weeks, through OGTT.

• Risk factors: previous GDM, BMI > 25, ethnicity (e.g., Hispanic, African American, Native American), family history of diabetes.

• Consequences: high blood pressure, increased risk of type 2 diabetes for mother; premature birth, macrosomia (large birth weight) for baby, and neonatal hypoglycemia.

• Human placental lactogen blocks insulin, leading to insulin resistance in the mother to provide more glucose to the fetus.

Glycosylated Proteins & HbA1c

• Reflects glucose concentration over 120 days (RBC lifespan), providing an estimate of average blood glucose levels over time.

• Normal level: 4-6%; >6.5% indicates uncontrolled DM and is used as a diagnostic criterion for diabetes.

• Method: HPLC (High-Performance Liquid Chromatography) is commonly used to measure HbA1c levels accurately.

Urinary Glucose (Glycosuria)

• Renal threshold exceeded when plasma glucose is high (>11mmol/L), leading to glucose spillage into the urine.

• Not reliable for monitoring DM because it only reflects glucose levels at a single point in time and is affected by renal function.

Microalbumin

• Increased urinary albumin indicates kidney damage, specifically diabetic nephropathy, an early sign of kidney dysfunction in diabetes.

Hypoglycaemia in Adults

• Plasma glucose <2.5 mmol/L, requiring prompt diagnosis and treatment to prevent neurological damage.

• Measure Plasma Insulin and C-peptide to differentiate causes of hypoglycemia and guide appropriate management.

C-Peptide Test

• Differentiates between type 1 and type 2 diabetes and helps determine the cause of endogenous hyperinsulinism.

• Type 1 DM: low or no C-peptide, indicating minimal insulin production by the pancreas.

• Type 2 DM: normal or high C-peptide, reflecting the pancreas's attempt to compensate for insulin resistance by producing more insulin.

Here's a breakdown of the tests mentioned in the provided note, what they assess, what they measure, and how to interpret the results: