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  • Diabetes Mellitus Pathophysiology
  • Diabetes Mellitus
    • Diabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.
    • The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both.
    • The effects of diabetes mellitus include long–term damage, dysfunction and failure of various organs.
  • Insulin secretion
  • Action of insulin
  • Action of insulin on CHO, Fat and Protein Metabolism
    • Carbohydrate
    • Facilitates the transport of glucose into muscle and adipose cells
    • Facilitates the conversion of glucose to glycogen for storage in the liver and muscle.
    • Decreases the breakdown and release of glucose from glycogen by the liver
    • Protein
    • Stimulates protein synthesis
    • Inhibits protein breakdown; diminishes gluconeogenesis
    • Fat
    • Stimulates lipogenesis- the transport of triglycerides to adipose tissue
    • Inhibits lipolysis – prevents excessive production of ketones or ketoacidosis
  • Major Reason for Insulin Secretion
    •  secretion
      • Elevated blood glucose levels
      • Increased fatty acids
      • GI hormones
      • Glucagon, growth hormone, cortisol
      • Insulin resistance
    •  secretion
      • Decreased blood glucose levels
      • Decreased food intake (fasting)
  • Hyperglycemia
    • an excessive amount of glucose circulates in the blood plasma
    • chronic levels exceeding 125 mg/dl can produce organ damage
  • Glucose Homeostasis
  • What goes wrong in Diabetes ?
    • Multitude of mechanisms
      • Insulin
        • Regulation
        • Secretion
        • Uptake or breakdown
      • Beta cells
        • damage
  • Type 1 Diabetes
    • Low or absent endogenous insulin
    • Dependent on exogenous insulin for life
    • Onset generally < 30 years
    • 5-10% of cases of diabetes
    • Onset sudden
      • Symptoms: 3 P’s: polyuria, polydypsia, polyphagia
  • Type 1 Diabetes cell
  • Metabolic defects in Type 1 Diabetes
    • Hyperglycemia and ketoacidosis
    • Hypertriacylglycerolemia
  • Type 2 Diabetes
    • Insulin levels may be normal, elevated or depressed
      • Characterized by insulin resistance,
      • diminished tissue sensitivity to insulin,
      • and impaired beta cell function (delayed or inadequate insulin release)
    • Often occurs >40 years
  • Type 2 Diabetic cell
  • Insulin Receptors
    • REMEMBER: the main action of the insulin receptor is to signal the cell to absorb glucose .
    • A decrease in insulin receptor signaling leads to type 2 diabetes mellitus.
      • Thus, the cells are not able to take up glucose, leading to hyperglycemia (an increase in glucose circulating in the blood), and all the resulting sequelae.
  • Type 2 Diabetes
    • Risk factors: family history, sedentary lifestyle, obesity and aging
    • Controlled by weight loss, oral hypoglycemic agents and or insulin
  • Metabolic defects in Type 2 Diabetes
    • Hyperglycemia
    • Hypertriacylglycerolemia ----- low levels of insulin ---- decreased activity of lipoprotein lipase ------ raised plasma level of VLDL
  • Long term effects of Diabetes Mellitus
    • Microvascular complications :-
    • - retinopathy
    • - nephropathy
    • - neuropathy
    • Macrovascular complications :-
    • - stroke
    • - cardiovascular disease
  • Screening/Diagnosis of Diabetes
  • Diabetic Process
    • Decreased insulin production or action
      • -> Increased glucose accumulates in blood
      • -> hyperglycemia
      • -> need to dilute glucose in circulating blood
      • -> fluids drawn from intracellular spaces to vascular bed
      • -> Thirst (polydipsia)
  • Diabetic Process
    • Thirst (polydipsia)
      • -> increased fluid intake
      • -> increased fluid volume
      • -> kidneys need to excrete excess volume
      • -> Polyuria (frequent urination)
        • Glycosuria (excretion of glucose into urine)
  • Diabetic Process:
    • Lack of glucose for energy/metabolism
      • -> cells starve
      • -> increased hunger ( Polyphagia )
      • -> increased food intake (weight gain)
    • No glucose to metabolize
      • -> protein metabolism (nitrogen imbalance)
      • -> fat metabolism: (ketone bodies (ketosis))
  • Diabetic Process:
    • Polydipsia, polyuria and polyphagia can lead to a fluctuations in blood glucose levels (hyperglycemia and hypoglycemia)
      • -> damage to small blood vessels throughout the body
      • -> serious impairment, especially kidneys, eyes, and heart
    • In pregnancy: decreased glucose to uterus and increased glucose to fetus
      • -> hypoglycemia at birth
  • Importance of glucose regulation
    • The brain: normally dependent on glucose for oxidative metabolism and function
    • Hypoglycemia
      • brain fuel deprivation
        • functional brain failure
          • corrected by raising plasma glucose concentrations
    • Hyperglycemia
      • Osmotic water loss (cellular and systemic)
        • Damages blood vessels
  • Hyperglycemia Symptoms
    • Classic Hyperglycemic Triad (the 3 P’s of diabetes):
      • Polydipsia
        • frequent thirst
        • excessive thirst
      • Polyuria
        • frequent urination
        • excessive urination
      • Polyphagia
        • frequent hunger
        • pronounced hunger
  • Additional Symptoms of Hyperglycemia
    • Blurred vision
    • Fatigue
    • Weight loss
    • Poor wound healing
    • Dry mouth
    • Dry or itchy skin
    • Impotence (male)
    • Recurrent infections
    • Kussmaul hyperventilation: deep, rapid breathing
    • Fruity/acetone smell on the breath
    • Cardiac arrhythmia
    • Stupor
    • Coma
    • Death
  • Glycemic Control
    • Glucose cycle: glucose in the bloodstream is made available to cells in the body
      • dependent upon
        • glucose entering the bloodstream
        • insulin allowing appropriate uptake into the cells of the body.
      • Both require management.
  • Glycemic Control
    • Management
      • highly intrusive
      • compliance is an issue
        • relies on user lifestyle change
        • often on regular sampling and measuring of blood glucose levels
    • Highly individual
  • Glycemic Control
    • Many of the long-term complications of diabetes, especially microvascular complications, result from many years of elevated blood glucose levels.
    • Good glycemic control, (70-130 mg/dl, or 3.9-7.2 mmol/L) is the important goal of diabetes care.
  • Glycemic control
    • The hemoglobin A1c (glycosylated hemoglobin) reveals “average” glucoses over the preceding 2-3 months.
    • In normal glucose metabolism, the glycosylated hemoglobin is usually 4-6% by the most common methods (normal ranges may vary by method).
  • Glycemic Control
    • &quot;Perfect glycemic control&quot;
      • glucose levels were always within the normal range (70-130 mg/dl, or 3.9-7.2 mmol/L)
    • “ Perfect” glycemic control very difficult, and even &quot;good glycemic control&quot; usually describes blood glucose levels that average somewhat higher than the normal range.
    • “ Poor glycemic control”
      • Persistently elevated blood glucose and glycosylated hemoglobin levels
      • May persist over months and years before severe complications develop.
  • Summary
    • Diabetes occurs when either there is inadequate insulin production in the pancreas or there is inadequate absorption of insulin into the cells.
    • Insulin is needed for metabolism of glucose for energy at the cellular level
    • Lack of glucose for metabolism  metabolism of fat and protein for energy, polyuria, polydipsia, and polyphagia (classic symptoms of diabetes) and others listed earlier
    • Chronic condition that can lead to multiple serious complications
    • Goal: glycemic control
  • Hypoglycemia symptoms
    • Shakiness
    • Nervousness
    • Sweating
    • Dizziness or light-headedness
    • Sleepiness
    • Confusion
    • Another clue to nocturnal hypoglycemia is postprandial hyperglycemia after breakfast
    • Difficulty speaking
    • Anxiety
    • Weakness
    • Hypoglycemia can also happen during sleep
      • crying out or having nightmares
      • finding pajamas or sheets damp from perspiration
      • feeling tired, irritable, or confused after waking up
  • Hypoglycemia
    • Hypoglycemia, also called low blood glucose or low blood sugar,
      • occurs when blood glucose drops below normal levels.