Insulin and Glucose Regulation

Counter-Regulating Hormones

• Increase in concentration in blood at low glucose concentrations
• Provide energy substrates from glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis

Insulin

• Pancreatic β-cells function as glucose sensors, secreting insulin in response to hyperglycemia
• Reduce insulin secretion if blood glucose decreases
• Synthesis involves preproinsulin, proinsulin, and insulin (51 AK) with C-peptide (connecting peptide)
• Functions:
  • Stimulate glucose uptake in muscle cells and enhance glycogenesis
  • Stimulate glucose uptake in adipose tissue cells and enhance lipogenesis
  • Inhibit gluconeogenesis and glycogenolysis in the liver

Diabetes Mellitus

• Systemic metabolic disorder characterized by chronic hyperglycemia with disturbances in CHO, fat, and protein metabolism
• Caused by relative or absolute deficiency in insulin and/or insulin resistance
• Complications:
  • Acute: diabetic ketacidosis, hyperosmolar hyperglycemic nonketotic, diabetic lactic acidosis, hypoglycemic coma
  • Chronic: macrovascular (atherosclerosis), microvascular (diabetic retinopathy, cataract, diabetic neuropathy, diabetic nephropathy)

Insulin-Dependent Diabetes Mellitus (IDDM)

• Type I or juvenile-onset diabetes
• Characterized by absolute deficiency of insulin due to massive autoimmune attack on β-cells
• Symptoms: polyuria, polydipsia, polyphagia
• Patients rely on exogenous insulin to restore metabolic control and avoid life-threatening ketoacidosis
• Complicated by ketoacidosis

Non-Insulin-Dependent Diabetes Mellitus (NIDDM)

• Type II or adult-onset diabetes
• Most common type, constituting 80-90% of diabetic cases
• Complications: same as IDDM, plus hypertriglyceridemia, hypercholesteremia, and low HDL

Gestational Diabetes Mellitus (GDM)

• Carbohydrate intolerance with onset or first recognition during pregnancy
• Incidence: 1-5% of pregnancies
• Patients often revert to normal glucose tolerance after delivery
• Requires treatment to normalize maternal blood glucose levels during pregnancy

Other Types of DM

• Latent Autoimmune Diabetes in Adults (LADA): a form of autoimmune diabetes diagnosed in individuals older than the usual age of onset of type 1 diabetes
• Laboratory monitoring of diabetic patients:
  • Monitoring of blood glucose: reduces incidence of chronic complications
  • HbA1c: assesses long-term compensation of a diabetic, indirect indicator of glycemia over life of erythrocytes
  • Urinary glucose test: correlates with glycemia only in patients with normal GFR
  • GFR: accurate measurement requires a substance with constant production and removal rate, such as creatinine
  • Creatinine: breakdown product of creatine and creatine phosphate, inversely proportional to GFR, but not sensitive and influenced by muscle mass and liver function
  • Blood Urea Nitrogen (BUN): formed in the liver as the end product of protein metabolism, eliminated via kidneys and GI tract

Serum Urea Levels

• Increase in conditions where renal clearance decreases (acute and chronic renal failure/impairment)
• Also increase in other conditions not related to renal diseases, such as:
  • Upper GI bleeding
  • Dehydration
  • Catabolic states
  • High protein diets
• Decrease in:
  • Starvation
  • Low-protein diet
  • Severe liver disease

BUN: Creatinine Ratio

• Useful to differentiate pre-renal from renal causes when BUN is increased
• In pre-renal disease, the ratio is close to 20:1
• In intrinsic renal disease, the ratio is closer to 10:1
• Upper GI bleeding can be associated with a very high BUN to creatinine ratio (sometimes >30:1)

Creatinine Clearance

• More sensitive than plasma creatinine at picking up small changes in renal function
• Removes the variables of diet and muscle mass
• Inconvenient, requiring 24hr urine collection plus serum sample
• Calculation: Evaluation of glomerular function

Cystatin C

• Small polypeptide produced by all nucleated cells at a constant rate
• Stable concentration in blood
• Renal handling of cystatin C differs from creatinine
• Not affected by:
  • Infections
  • Inflammatory or neoplastic states
  • Body mass
  • Diet
  • Drugs
• Useful for monitoring progression of renal disease, assessing therapeutic response, and estimating cardiovascular risk

Glomerular Filtration Rate (GFR)

• Volume of blood filtered across glomerulus per unit time
• Measurement based on a theoretical concept of clearance
• Requires a substance that is:
  • Freely filtered by glomeruli
  • Not secreted or reabsorbed in tubules
  • Produced and removed from the body with a constant rate
• Creatinine is close to fulfilling these criteria

Creatinine

• Breakdown product of creatine and creatine phosphate
• Released from skeletal muscle at a steady rate
• Not metabolized or excreted from the body other than by the kidney
• Can measure its clearance from plasma or excretion in urine
• Inversely proportional to GFR
• Limitations:
  • Not sensitive (serum creatinine only increases above normal when kidney function drops by half)
  • Influenced by:
    • Muscle mass size
    • Food intake (meat)
    • Liver function (synthesis of creatine)

Blood Urea Nitrogen (BUN)

• Nitrogen-containing compound formed in the liver as the end product of protein metabolism
• About 85% of urea is eliminated via kidneys; the rest is excreted via the GI tract
• Hormonal functions:
  • Produces erythropoietin, which helps promote erythropoiesis in bone marrow
  • Plays a role in calcium metabolism by activating vit.D

Renal Function Test (RFT)

• Group of tests used to assess the functions of the kidney
• Used to:
  • Screen for, detect, evaluate, and monitor acute and chronic kidney diseases
  • Monitor the response of kidneys to treatment or progression of renal disease
  • Evaluate kidney function in patients with other conditions that can harm the kidneys, such as diabetes or high blood pressure

Nephron

• Functional unit of the kidney
• Each of the approximately one million nephrons is made up of five main functional segments
• The principal function of the glomeruli is to filtration, which is permeable to water and low molecular weight substances, but impermeable to macromolecules like proteins.