Diabetes - Functional anatomy, physiology and investigations Flashcards Preview

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Flashcards in Diabetes - Functional anatomy, physiology and investigations Deck (20):

What hormones maintain blood glucose concentrations? When are they secreted?

Glucose enters the circulation from the liver and is taken up by peripheral tissues, particularly skeletal muscle. The brain relies on glucose as its principal metabolic fuel because it cannot oxidise free fatty acids.

When intestinal glucose absorption decreases between meals, hepatic glucose output is increased in response to low insulin levels and increased levels of glucagon and adrenaline. The liver produces glucose by gluconeogenesis and glycogenolysis.

After meals, blood insulin levels rise in response to a rise in blood glucose. Insulin is an anabolic hormone and is secreted from pancreatic beta cells into the portal circulation. Insulin lowers blood glucose by suppressing hepatic glucose production and stimulating glucose uptake in skeletal muscle and fat.


How does insulin affect fat metabolism?

Insulin stimulates lipogenesis (formation of lipids) and inhibits lipolysis. Lipolysis is stimulated by catecholamines and liberates FFAs, which can be oxidised by many tissues. Their partial oxidation in the liver produces ketone bodies, which can be oxidised by many tissues as fuel. However, the rate of utilisation of ketone bodies by peripheral tissues is limited, and when production by the liver exceeds removal, hyperketonaemia results. Ketogenesis is enhanced by insulin deficiency and release of counter regulatory hormones that stimulate lipolysis.


What is the pathology of type 1 diabetes?

Type 1 diabetes (formerly "insulin dependent diabetes mellitus") is associated with profound insulin deficiency requiring replacement therapy.

Type 1 diabetes is a slowly progressive T cell mediated autoimmune disease, leading to destruction of the insulin secreting B cells. Classical symptoms of diabetes only occur when 70-90% of B cells have been destroyed. Pathology shows insulitis (infiltration of the islets with mononuclear cells), in which B cells are destroyed, but cells secreting glucagon and other hormones remain intact.


Are auto-antibodies useful in screening for type 1 diabetes?

Islet cell antibodies can be detected BEFORE clinical diabetes develops and disappear with increasing duration of diabetes; however, they are not suitable for screening or diagnostic purposes.

Glutamic acid decarboxylase (GAD) antibodies may have a role in identifying late onset type 1 autoimmune diabetes in adults (LADA). Type 1 diabetes is associated with other autoimmune disorders, including thyroid disease, ceoliac disease, Addison's disease, pernicious anaemia and vitiligo.


How do genetic factors play a role in the aetiology of type 1 diabetes?

Genetic factors account for about 1/3 of the susceptibility to type 1 diabetes, with 35% concordance between monozygotic twins. HLA DR3 and or DR4 on chromosome 6 are associated with increased susceptibility to type 1 diabetes. Defective presentation of autoantigens derived from B cells probably underlies the autoimmunity.


What environmental factors may play a role in type 1 diabetes?

Reduced exposure to microorganisms in early childhood may limit maturation of the immune system and increase susceptibility to autoimmune disease (the hygeine hypothesis).

Viral infections including mumps, Coxsackie B4, retrovirus, congenital rubella, cytomegalovirus and EBV might cause some forms of type 1 diabetes. Bovine serum albumin (BSA) has been implicated in triggering type 1 diabetes, since infants who are given cows milk are more likely to develop type 1 diabetes in later life than those who are breastfed.

Stress may also be implicated.


What metabolic disturbances can occur in patients with type 1 diabetes?

Patients with type 1 diabetes present when adequate insulin secretion can no longer be sustained. High glucose levels may be toxic to the remaining B cells so that profound insulin deficiency rapidly ensues.

Lack of insulin has multiple metabolic sequelae:
1) Decreased anabolism - hyperglycaemia leads to glycosuria and dehydration which in turn induces secondary hyperaldosteronism. This encourages urinary loss of K+
- hyperglycaemia can cause fatigue
- glycosuria can lead to vulvitis and balanitis (due to bacterial colonisation)
- osmotic diuresis causes polyuria, polydypsia, tacchycardia and hypotension, and if salt depletion is severe can cause death

2) Increased catabolism - lack of insulin promotes increased glycogenolysis, gluconeogenesis and lipolysis which causes wasting and weight loss
- unrestrained proteolysis and lipolysis causes ketogenesis, hyperketonaemia and ketoacidosis
- ketoacidosis causes DKA: hyperventilation (Kussmaul's breathing), peripheral vasodilatation, hypothermia, hypotension, hyperkalaemia (due to cellular shift of H+ ions in exchange for K+)


What is the pathophysiology of type 2 diabetes?

In type 2 diabetes, patients retain some capacity to secrete insulin but there is a combination of resistance to the actions of insulin followed by impaired pancreatic B cell function, leading to "relative" insulin deficiency.

1) Insulin resistance - excessive production of glucose in the liver and under utilisation of glucose in skeletal muscle result from resistance to the actions of insulin. Type 2 diabetes is often associated with other medical disorders, which when they coexist are termed "metabolic syndrome", with a predisposition to insulin resistance being the primary problem. It is strongly associated with macrovascular disease (coronary, cerebral, peripheral) and an excess mortality.

"Central" adipose tissue may amplify insulin resistance by releasing FFAs and hormones. Sedentary people are more insulin resistant than active people with the same degree of obesity. Inactivity down regulates insulin sensitive kinases and may also increase the accumulation of FFAs within skeletal muscle. Exercise also allows non insulin dependent glucose uptake into muscle, reducing the "demand" on the pancreatic B cells to produce insulin.

2) Pancreatic B cell failure - deposition of amyloid in pancreatic islet cells is found in type 2 diabetes. While B cell numbers are typically reduced by 20-30% in type 2 diabetes, B cell mass is unchanged and glucagon secretion is increased which may contribute to the hyperglycaemia


How does genetic predisposition play a role in type 2 diabetes?

Genetic factors are important in the aetiology of type 2 diabetes; monozygotic twins have concordance rates approaching 100%. However, many genes are involved and the chance of developing diabetes is also influenced by environmental factors.


What are the features of insulin resistance (metabolic) syndrome?

- Hyperinsulinaemia
- Type 2 diabetes or impaired glucose tolerance test
- Hypertension
- low HDL cholesterol; elevated triglycerides
- Microalbuminuria
- Increased fibrinogen, uric acid
- Central (visceral) obesity
- Increased sympathetic activity


What environmental factors are important in type 2 diabetes?

Type 2 diabetes is associated with overeating, especially when combined with obesity and under activity. However, only a minority of obese people develop diabetes. Obesity probably acts as a diabetogenic factor in those who are genetically predisposed both to insulin resistance and to B cell failure. The risk of developing type 2 diabetes increases ten fold in people with a BMI >30.


Other type 2 diabetes risk factors

1) Age - type 2 diabetes is principally a disease of the middle aged and elderly. In the UK it affects 10% of the population over 65 and over 70% of all cases of diabetes occur after the age of 50

2) Pregnancy - during normal pregnancy, insulin sensitivity is reduced through the action of placental hormones. Repeated pregnancy may increase the likelihood of developing irreversible diabetes, particularly in obese women. Around 80% of women with gestational diabetes ultimately develop permanent diabetes


What metabolic disturbances can occur in type 2 diabetes?

Only small amounts of insulin are required to suppress lipolysis, and some glucose uptake is maintained in muscle, so that weight loss and ketoacidosis are rare (but can happen). Glycosuria occurs when blood glucose concentration exceeds the renal threshold (10 mmol/L). The severity of the classical "osmotic" symptoms of polyuria and polydipsia is related to the degree of glycosuria. In type 2 patients, hyperglycaemia develops slowly and the renal threshold for glucose rises, so that osmotic symptoms are usually mild. Thus, patients are often asymptomatic, but usually present with a long history of fatigue, with or without osmotic symptoms.

In some patients, presentation is late and pancreatic B cell function has declined to the point where there is profound insulin deficiency. These patients may present with weight loss, although ketoacidosis remains rare. Intercurrent illness, e.g. with infections, increases the production of counter regulatory hormones (cortisol, growth hormone, catecholamines), resulting in more severe hyperglycaemia and dehydration (HONK). Dyslipidaemias are also common in patients with type 2 diabetes.


What investigations are used to monitor diabetes?

1) Urine testing - glucose, ketones, protein
2) Blood testing - HbA1c, glucose, lipids


What glucose abnormalities are checked for on urine dipstick in diabetes? What is a "lag storage"?

Sensitive glucose specific dipsticks are used to detect GLYCOSURIA, ideally on urine passed 1-2 hrs after a meal, since this will detect more cases of diabetes. However, glycosuria can be due to a low renal threshold. This is a benign condition, common during pregnancy and in young people. Glycosuria always warrants further assessment by blood testing.

In some individuals a rapid but transitory rise of blood glucose follows a meal and the concentration exceeds the normal renal threshold. This response is benign and is described as a "lag storage" blood glucose curve or alimentary glycosuria. It may occur after gastric surgery, or in hyperthyroidism, peptic ulcertaion or hepatic disease. Glycosuria is common in normal pregnancy (increased glomerular filtration rate). However, it should never be ignored and gestational diabetes should be excluded.


What causes ketonuria?

Ketonuria (ketones in the urine) may be found in normal people who have been fasting, exercising, or vomiting repeatedly, or those on a high fat, low carbohydrate diet. Ketonuria is therefore not pathognomonic of diabetes, but if it is associated with glycosuria then diabetes is highly likely.


What level of urinary albumin can dipsticks detect and what does this indicate?

Dipstick testing will detect urinary albumin >300mg/l and can indicate renal disease or urinary infection in people with diabetes.


Which type of blood glucose measure is most reliable to measuring serum glucose?

Capillary blood glucose can be easily measured and used to monitor diabetes treatment. Glucose concentrations are lower in venous than in arterial or capillary (fingerprick) blood. Whole blood glucose concentrations are lower than plasma concentrations because red blood cells contain relatively little glucose. Venous plasma values are the most reliable for diagnostic purposes.


Why are blood lipids measured in diabetic patients>

The concentration of serum lipids - total, LDL and HDL cholesterol and triglycerides - is another important index of metabolic control in diabetic patients and should be measured at diagnosis and regularly thereafter.


What is glycated haemoglobin?

Glycated haemoglobin (Hb) provides an accurate and objective measure of glycaemic control over a period of 2 months. It is used to assess glycaemic control, but is not sufficiently sensitive to make a diagnosis of diabetes.

The non enzymatic covalent attachement of glucose to Hb (glycation) increases the amount in the HbA1c fraction relative to non glycated adult Hb (HbA0). The rate of formation of HbA1c is directly proportional to the blood glucose concentration; a rise of 1% in HbA1c corresponds to an increase of 2mmol/L in blood glucose. HbA1c concentration reflects blood glucose over the erythrocyte lifespan (120 days) but is affected more by recent events.

HbA1c estimates may be erroneously diminished in anaemia and pregnancy, and may be difficult to itnerpret in uraemia and haemoglobinopathy. In clinical practice, HbA1c is measured once or twice tearly to assess glycaemic control and provides an index of risk of developing diabetic complications.

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