Diabetes Mellitus

Pathophysiology

Diabetes MellitusDiabetes 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 DiabetesFasting Blood Glucose

Significance Action

< 110 Normal Retest in 3 years

>110 & <126

IGT 1. Additional testing

2. Check risk factors

3. MNT > 126 Diabetes

Likely 1. Confirm by 2nd FBG 2. Treat DM

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• "Perfect glycemic control"

– 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 "good glycemic control" 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.

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