Metabolic Changes In Diabetes Mellitus

Question 1

What are the types of diabetes?

Answer 1

• Includes a heterogenous group of multifactorial disorders characterized by the presence of hyperglycemia (high blood glucose levels) that result from defects in secretion of insulin OR action of insulin OR both
• Type I diabetes (Insulin dependent diabetes mellitus)
• Type II diabetes (Non-insulin dependent diabetes mellitus)

• Gestational diabetes
– Diabetes during pregnancy and blood glucose levels normalize following delivery – Higher incidence of fetal malformations, macrosomia and neonatal
hypoglycemia

• Secondary diabetes:
– Secondary to other disorders like excessive secretion of cortisol, growth
hormone, chronic pancreatic disorders

Question 2

Describe type 1 Diabetes

Answer 2

• Insulin dependent diabetes mellitus (IDDM)/ Juvenile onset diabetes mellitus
• Autoimmune destruction of the β-cells of islets of pancreas, resulting in destruction of the islet cells and a marked reduction in insulin secretion
• Insulin levels are very low or absent
• Represents about 10% of all patients with diabetes mellitus
• Presents during adolescence (young adults)
• Patients have to be on life-long insulin supplementation to prevent the complications of diabetes

Question 3

Describe type 2 diabetes mellitus

Answer 3

• Non-insulindependentdiabetesmellitus(NIDDM)
• Obesity (Syndrome X/ Metabolic syndrome/ insulin resistance syndrome) is
an important risk factor for development of type II diabetes mellitus and
insulin resistance

• Target tissues for insulin (liver, skeletal muscle & adipose tissue) do not
respond to circulating insulin (insulin resistance) and there is a decrease in
insulin secretion with time (beta cell dysfunction)

• Circulating insulin levels are high/ normal/ low (depending on the stage of the
disease)

• Usuallyrespondtooralhypoglycemicagentsandinsulinmayberequiredin
the later stages of the disorder

• Type II diabetic patients have
– Insulin resistance
Beta cell dysfunction and reduced secretion of insulin

Question 4

What are the presenting features of diabetes?

Answer 4

• Classical triad: Polyphagia, Polydipsia, and Polyuria are more common with type I diabetes
• Weight loss may be observed in many patients (type I) – due to accelerated lipolysis and muscle proteolysis
• Many of patients with type II diabetes are obese (insulin resistance)
• Diabetes mellitus affects carbohydrate, lipid and protein metabolism

• Decreased secretion of insulin/ ineffective insulin action →
Hyperglycemia

Question 5

What is the mechanism of hyperglycemia in diabetes mellitus (type 1 and 2)?

Answer 5

Increased gluconeogenesis in liver

Decreased number of GLUT4 in peripheral tissues

Decreased number of insulin receptors/post receptor defects

Decreased secretion of insulin from the pancreas

Question 6

Why is therehyperglycemia?

Answer 6

• In an uncontrolled diabetic the insulin/ glucagon ratio is low

• Key gluconeogenic enzymes are activated
(induced)
– Phosphoenolpyruvate carboxykinase (PEPCK)
– Pyruvate carboxylase
– Fructose 1,6- bisphosphatase (low levels of fructose 2,6-bisphosphate)
– Glucose 6-phosphatase
– Amino acids from muscle proteolysis are used for
gluconeogenesis

• Glycolysis is inhibited (liver)
• Glycogenesis is inactive (liver and muscle

Question 7

Describe insulin dependent uptake of glucose in adipose tissue and muscle (GLUT-4)

Answer 7

The deficiency of insulin/ insulin resistance results in decreased number of GLUT4 in peripheral tissues (muscle and adipose tissue), contributing to hyperglycemia.

Exercise results in an insulin independent uptake of glucose by muscle via AMP-kinase pathway

Question 8

What is the basis of glycosuria and polyuria?

Answer 8

Glucose is completely reabsorbed in the renal tubule. Glucose is absent in urine in a normal person

In hyperglycemia, a large amount of glucose is filtered, that exceeds the reabsorptive capacity of the tubule. Glucose is osmotically active (holds water), resulting in ‘polyuria’ (Osmotic diuresis)

Question 9

Describe ketosis in diabetes type 1

Answer 9

• Insulin deficiency results in uncontrolled adipose tissue lipolysis (Hormone sensitive lipase is active due to low insulin/glucagon ratio; HS lipase is in the phosphorylated form)
• There is increased free fatty acid delivery to the liver

• Increased rates of β-oxidation (Active CPT-1 and
increased free fatty acids), results in the formation of acetyl CoA, that is used for ketone body synthesis (active mitochondrial HMG CoA synthase and HMG CoA lyase)

• Ketogenesis in liver&raquo_space; peripheral utilization of ketone bodies
The ketone body formed in highest concentration is 3-
hydroxybutyrate (major ketone body)

Question 10

How does diabetes lead to metabolic acidosis?

Answer 10

• Excessive ketone bodies are excreted in urine (ketonuria) – can be detected by dipsticks. 3-hydroxybutyrate and acetoacetate in blood and urine
• Increased formation of 3-hydroxybutyrate and acetoacetate; Ketone bodies are weak acids; Bicarbonate levels fall as they are used for buffering the excessive protons produced (Metabolic acidosis)
• Increased anion gap (due to very high levels of ketone bodies)
• pH: Low; HCO3-: Low; PCO2: Low

• Compensation by the respiratory system→ ↑rate and depth of ventilation
(hyperventilation) – Kussmaul breathing

• Kidneys can also compensate by excreting an acidic urine after 3-5 days (increased
ammonium and phosphate excretion in urine)

• Ketone bodies are also lost via lungs (acetone) – ‘fruity odor of breath’
• The metabolic acidosis can be severe and may worsen coma (Ketoacidotic coma)

Question 11

What are the effects of hyperglycemia?

Answer 11

• Elevated blood glucose levels → Glycosuria results in increased water loss → Dehydration → Stimulation of the thirst center (polydipsia)
• Coma is usually due to hyperglycemia (Osmotic effect: Water moves out of ICF resulting in neuronal dehydration) and is worsened by metabolic acidosis
• Infection/ illness exacerbates the predisposition to ketoacidosis (insulin requirements increase during an episode of illness due to insulin resistance due to stress)

• Failure to comply with insulin therapy may also result in ketoacidosis in type I diabetics
Ketoacidosis may be the presenting feature in many patients with type I diabete

Question 12

What fluid and electrolyte changes are made due to diabetes?

Answer 12

Dehydration – Due to loss of water due to osmotic diuresis due to glucosuria (glycosuria)

• Changes in serum potassium: (Hyperkalemia) Insulin deficiency and acidosis result in a shift of potassium from the ICF to the ECF. This results in loss of potassium in urine (Whole body potassium is reduced, even though serum potassium may be high).

 When insulin is injected during the treatment, potassium moves back into the ICF – Since potassium reserves are low, patient is in danger of hypokalemia (requires close monitoring)

Question 13

What causes the hyperosmolar hyperglycemic state?

Answer 13

• More common in Type II diabetes mellitus
• Typically precipitated by an acute illness/ infection (insulin resistance)

• Hyperglycemia: Plasma glucose levels are markedly elevated (>600mg/dL)

• Hyperosmolarity: Osmolarity of blood is increased due to the high blood
glucose levels (>320 mOsm/L; Normal-280-300)

• There is polyuria (glycosuria) – excessive losses of water in urine –
osmotic diuresis (Polyuria)

• Patients have a low blood volume as a result of polyuria (severe
dehydration)

• Ketone body production is NOT significant (compare to diabetic ketoacidosis).

• Why is ketosis NOT a prominent feature of type II diabetes mellitus??? – Patients have some insulin secretion which inhibits ketogenesis
Metabolic acidosis NOT commonly associated

Question 14

What are the effects of hyperosmolar hyperglycemic state in diabetes?

Answer 14

• Intracellular dehydration in the neurons, as ICF water moves into ECF (High plasma osmolarity; Glucose is osmotically active) → Changes in hydration of neurons → Neurological deficits, unconsciousness (coma)
• Neurological changes usually revert back to normal on management of hyperglycemia
• Fluid balance to be restored during management to correct the dehydration

Question 15

What are the chronic complications of diabetes?

Answer 15

• Chronic complications are common to type-I and type-II
diabetes mellitus

• The incidence of chronic complications is higher in patients who have higher plasma glucose levels and higher HbA1c levels (Poor glycemic control)
• Microvascular: Eyes, retina, neurons, kidney

• Macrovascular: Atherosclerosis and its complications due to
dyslipidemia

Question 16

What are microvascular complications of diabetes?

Answer 16

• Neuropathy, nephropathy and retinopathy are the microvascular complications of diabetes
• Occurs in tissues which do not require insulin for glucose entry (for example retina, nervous tissue, lens, nephrons)

• Mechanisms of complications: Related to high intracellular glucose and/or its metabolites
– Sorbitol formation
– Nonenzymatic glycation of proteins (Advanced glycation end products: AGE) – Hexosamine pathway
– DAG and protein kinase C

• All the processes are dependent on the plasma glucose concentration

Question 17

How does sorbitol lead to microvascular complications?

Answer 17

• In the lens, nerve and kidney, sorbitol formed is osmotically active and results in cell swelling due to water retention

• The formation of sorbitol is directly related to the plasma glucose levels
• Enzyme: Aldose reductase
• Increased sorbitol formation in the lens results in increased water content of the lens that can result in vision changes and cataracts (due to changes in solubility of proteins).
• Sorbitol accumulation in neurons affects function of nerves

Question 18

What is the significance Of advanced glycation end products (AGE)?

Answer 18

• Non-enzymatic addition of glucose to intracellular and extracellular proteins (Process similar to formation of HbA1c)
• Glycation of proteins results in cross-linking of glycated proteins and altered function – leading to glomerular dysfunction, endothelial damage and changes in extracellular matrix
• AGE modified proteins are more prone for oxidative damage

Question 19

What are the effects of AGEs?

Answer 19

• AGEs (advanced glycation end products) alter metabolism and function of neuronal proteins
• AGEs bind to their receptors (RAGEs) and cause release of proinflammatory molecules
• Alteration of the glomerular basement membrane proteins of nephron – loss of albumin in urine (detected as microalbuminuria)

Question 20

What are the microvascular complications of AGEs?

Answer 20

Foot ulcers: Painless (neuropathy and peripheral vascular disease are contributory factors)

Increased loss of albumin in urine in the initial stages (microalbuminuria); Earliest indicator of diabetic renal involvement

In later stages, there may be development of renal failure

Question 21

What are the microvascular complications of DAG pathway?

Answer 21

• Hyperglycemia increases the formation of DAG (Diacylglycerol) which activates protein kinase C
• Activation of protein kinase C increases transcription of proteins like fibronectin, collagen and proteins of the extracellular matrix
• This results in changes in the neurons, nephrons and endothelium of blood vessels

Question 22

How can the hexosamine pathway lead to microvascular complications?

Answer 22

• Hyperglycemia increases flux through the hexosamine pathway and forms fructose 6-phophate and hexosamines (glucosamine; aminosugars)
• Hexosamines are substrates for proteoglycan synthesis and glycoprotein synthesis
• This results in altered function of these components and may cause altered expression of certain growth factors

Question 23

Describe macrovascular complications of diabetes due to dyslipidemia

Answer 23

• Accelerated atherosclerotic changes resulting in cardiovascular disease or stroke (Macrovascular complications)
• Patients with both types of diabetes have hypertriglyceridemia (↑ circulating triglycerides). There is increased chylomicrons and VLDL in the circulation.
• Due to the decreased action of endothelial lipoprotein lipase (lipoprotein lipase is induced by insulin)
• Obese subjects with diabetes mellitus also may have hypertension, dyslipidemia and hypercoagulability (insulin resistance/ syndrome X) – all these factors increase the risk of cardiovascular disease in diabetes

• AtherogenicsmalldenseLDLlevelsarehigherintype-IIdiabetics
• HDL levels are lower in type-II diabetics
• AGEs are also implicated in atherogenesis (glycation of LDL and glycation of
proteins in the blood vessel wall)

Question 24

What is the significance of HBA1c?

Answer 24

• HbA1c is the non-enzymatic glycation of hemoglobin (HbA1c levels depends on the blood glucose concentration)
• HbA1c levels are an indicator of long term glucose levels (Over the past 3-4 months)
• Patients that have poor blood glucose control (reflected by high HBA1C levels), have been observed to have a higher incidence of complications (microvascular and macrovascular)
• Optimal blood glucose control reduces the incidence of complications
• HbA1c is increasingly also used for the diagnosis of diabetes mellitus
• Levels greater than 6.5% are indicative of diabetes mellitus