Diabetes mellitus

Diabetes Mellitus

Dr.
Bashar Shaker
4/4/2016
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Diabetes mellitus is a clinical syndrome characterised by an increase in plasma blood glucose (hyperglycaemia).
Diabetes has many causes but is most commonly due to type 1 or type 2 diabetes.
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Pancreas

Exocrine
Enddocrine Alpha cells
Beta cells Insulin
Insulin Entry of glucose
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Metabolic actions of insulinللاطلاع

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للاطلاع

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Type 1 diabetes is caused by autoimmune destruction of insulin-producing cells (B cells) in the pancreas, resulting in absolute insulin deficiency
• Type 2 diabetes is characterised by resistance to the action of insulin and an inability to produce sufficient insulin to
• overcome this ‘insulin resistance’.
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Prevalence (%) of diabetes in those aged 20–79 years, 2011

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Globally, diabetes caused 4.6 million deaths in 2011, and health-care expenditure attributed to diabetes was estimated to be at least US$465 billion, or 11% of total health-care expenditure.
The incidence of diabetes is rising. Globally, it is estimated that 366 million people had diabetes in 2011 (approximately 8.3% of the world population, or 3 new cases every 10 seconds), and this figure is expected to reach 552 million by 2030.
Type 2
Environmental factors such as greater longevity, obesity, unsatisfactory diet, sedentary lifestyle,increasing urbanisation and economic development .
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Aetiology and pathogenesis of diabetes

In both of the common types of diabetes, environmental factors interact with genetic susceptibility to determine which people develop the clinical syndrome, and the timing of its onset.
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Type 1 diabetes
Type 1 diabetes is a T cell-mediated autoimmune disease involving destruction of the insulin-secreting β cells in the pancreatic islets
80–90% of the functional capacity
Type 1 diabetes is associated with other autoimmune disorders
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Genetic factors account for about one-third of the susceptibility to type 1 diabetes, the inheritance of which is polygenic .

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Risk of type 1 diabetes among first-degreerelatives of patients with type 1 diabetesللاطلاع
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Environmental predisposition

The concordance rate between monozygotic twins is less than 40% , and wide geographic and seasonal variations in incidence.
Direct toxicity to B cells or by stimulating an autoimmune reaction directed against B cells.
Potential candidates fall into three main categories:
viruses, specific drugs or chemicals, and dietary constituents.
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Type 2 diabetes

Thought to be caused by resistance to insulin action.
obesity is a major cause
Inactivity


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Environmental and other risk factors

Diet and obesity
Tenfold in people with a body mass index (BMI) of more than 30 kg/m2
Age
Type 2 diabetes is more common in 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 years.
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Aetiological classification of diabetes mellitus

Type 1 diabetes
• Immune-mediated
• Idiopathic
Type 2 diabetes
Other specific types
• Genetic defects of β-cell function
• Genetic defects of insulin action (e.g. leprechaunism,
lipodystrophies)
• Pancreatic disease


Excess endogenous production of hormonal antagonists to insulin, e.g.
Growth hormone – acromegaly,Glucocorticoids – Cushing’s syndrome
Glucagon – glucagonom, ,Catecholamines – phaeochromocytoma
Thyroid hormones – thyrotoxicosis
• Drug-induced (e.g. corticosteroids, thiazide diuretics, phenytoin)
• Uncommon forms of immune-mediated diabetes
• Associated with genetic syndromes Gestational diabetes
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Symptoms of hyperglycaemia

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Classical features of type 1 and type 2 diabetes

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To make the diagnosis of diabetes, the blood glucose concentration should be estimated using an accurate laboratory method rather than a portable technique.
Glucose concentrations are lower in venous than 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 usually the most reliable for
diagnostic purposes .
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Glycated haemoglobin
In diabetes, the slow non-enzymatic covalent attachment of glucose to haemoglobin (glycation) increases the amount in the HbA1 (HbA1c) fraction relative to nonglycated adult haemoglobin (HbA0).
Although HbA1c concentration reflects the integrated blood glucose control over the lifespan of erythrocytes (120 days), HbA1c is mostsensitive to changes in glycaemic control occurring in
the month before measurement.
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Conversion between DCCT and IFCC unitsfor HbA1cللاطلاع

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Establishing the diagnosis of diabetes

Glycaemia can be classified into three categories: normal, impaired (pre-diabetes) and diabetes
The glucose cut-off that defines diabetes is based upon the level above which there is a significant risk of microvascular complications (retinopathy, nephropathy, neuropathy).
People categorised as having pre-diabetes have blood glucose levels that carry a negligible risk of microvascular complications but are at increased risk of developing diabetes. Also, people with pre-diabetes have increased risk of cardiovascular disease (myocardial infarction, stroke and peripheral vascular disease).
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Diagnosis of diabetes and pre-diabetes

Diabetes is confirmed by either:
• Plasma glucose in random sample or 2 hrs after a 75 g glucose load ≥ 11.1 (200 mg/dL) or
• Fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL)
In asymptomatic patients, two diagnostic tests are required to confirm diabetes.
‘Pre-diabetes’ is classified as:
• Impaired fasting glucose = fasting plasma glucose ≥ 6.0
(108 mg/dL) and < 7.0 mmol/L (126 mg/dL)
• Impaired glucose tolerance = fasting plasma glucose< 7.0 mmol/L (126 m g/dL) and 2-hr glucose after 75 g oral glucose drink 7.8–11.1 mmol/L (140–200 mg/dL)
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How to perform an oral glucosetolerance test (OGTT)للاطلاع
Which patients to test
• Fasting plasma glucose 6.1–7.0 mmol/L (110–126 mg/dL)
• Uncertainty about the diagnosis of diabetes
Preparation before the test
• Unrestricted carbohydrate diet for 3 days
• Fasted overnight for at least 8 hrs
• Rest for 30 mins
• Remain seated for the duration of the test, with no smoking
Sampling
• Measure plasma glucose before and 2 hrs after a 75 g oral
glucose drink
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Management

The aims of management are to improve symptoms of hyperglycaemia and to minimise the risks of long-term microvascular and macrovascular complications.
Treatment methods for diabetes include dietary/lifestyle modification, oral anti-diabetic drugs and injected therapies.
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Blood glucose targets vary according to individual circumstances, but, in general,

Pre-meal values between 4 and 7 mmol/L (72 and 126 mg/dL) and 2-hour post-meal values between 4 and 8 mmol/L represent optimal control.
HbA1c target depends on the individual patient.
Early on in diabetes (i.e. patients managed by diet or one or two oral agents), a target of 48 mmol/mol (6.5%) or less may be appropriate.
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Dietary management of diabetes
Aims of dietary management
• Achieve good glycaemic control
• Reduce hyperglycaemia and avoid hypoglycaemia
• Assist with weight management:
Weight maintenance for type 1 diabetes and non-obese
type 2 diabetes
Weight loss for overweight and obese type 2 diabetes
• Reduce the risk of micro- and macrovascular complications
• Ensure adequate nutritional intake
• Avoid ‘atherogenic’ diets or those that aggravate
complications, e.g. high protein intake in nephropathy
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Dietary constituents and recommended % of energy intake

Carbohydrate: 45–60%
Sucrose: up to 10%
• Fat (total): < 35%
• Protein: 10–15% (do not exceed 1 g/kg body weight/day)
• Fruit/vegetables: 5 portions daily
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Biguanides(Metformin)
It is employed as first-line therapy in all patients who tolerate it, and its use is maintained when additional agents are added as glycaemia deteriorates .
Metformin is usually introduced at low dose (500 mg twice daily) to minimise the risk of gastrointestinal side effects.
The usual maintenance dose is 1 g twice daily.
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Biguanides(Metformin)

Metformin reduces hepatic glucose production,
may also increase insulin-mediated glucose
uptake, and has effects on gut glucose uptake and utilisation.
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Sulphonylureas

Promote pancreatic B-cell insulin secretion.
Sulphonylureas are an effective therapy for lowering blood glucose and are often used as an add-on to metformin, if glycaemia is inadequately controlled on metformin alone .
The main adverse effects of sulphonylureas are weight gain and hypoglycaemia.
Glibenclamide, gliclazide ,glimepiride and
glipizide.
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Alpha-glucosidase inhibitors

The Alpha -glucosidase inhibitors delay carbohydrate absorption in the gut by inhibiting disaccharidases.
Acarbose and miglitol are available and are taken with each meal.
Both lower post-prandial blood glucose and modestly improve overall glycaemic control.
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Thiazolidinediones
Enhance the actions of endogenous insulin.
Pioglitazone
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Incretin-based therapies: DPP-4inhibitors and GLP-1 analogues

The incretin effect is the augmentation of insulin secretion seen when a glucose stimulus is given orally rather than intravenously, and reflects the release of incretin peptides from the gut .
The incretin hormones are primarily glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). These are rapidly broken down by the peptidase DPP-4 (dipeptidyl peptidase 4).
Sitagliptin; others now available include vildagliptin, saxagliptin and linagliptin.
GLP-1 receptor agonists have to be given by subcutaneous injection
Delays gastric emptying and, at the level of the hypothalamus,
decreases appetite.
Exenatide (twice daily), exenatide MR (once weekly) and liraglutide (once daily)..
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SGLT2 inhibitors

Glucose is filtered freely in the renal glomeruli and reabsorbed in the proximal tubules. SGLT2 is involved in reabsorption of glucose. Inhibition results in approximately 25% of the filtered glucose not being reabsorbed, with consequent
glycosuria.

Dapagliflozin

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Insulin therapy
Insulin was discovered in 1921
Until the 1980s, insulin was obtained by extraction
and purification from pancreata of cows and pigs
Recombinant DNA technology enabled large-scale production of human insulin.
More recently, the amino acid sequence of insulin has been altered to produce analogues of insulin, which differ in their rate of absorption from the site of injection.

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Duration of action (in hours) of insulin preparationsللاطلاع

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Insulin dosing regimensللاطلاع

The choice of regimen depends on the desired degree of
glycaemic control, the severity of underlying insulin
deficiency, the patient’s lifestyle, and his or her ability
to adjust the insulin dose.
Most people with type 1 diabetes require two or more injections of insulin daily.
In type 2 diabetes, insulin is usually initiated as a once-daily long acting insulin, either alone or in combination with oral hypoglycaemic agents.
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Insulin dosing regimensللاطلاع
Twice-daily administration of a short-acting and
intermediate-acting insulin (usually soluble and isophane
insulins), given in combination before breakfast
and the evening meal, is the simplest regimen and is still
used commonly in many countries.
Initially, two-thirds of the total daily requirement of insulin is given in the morning in a ratio of short-acting to intermediate-acting of 1 : 2, and the remaining third is given in the evening.
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Insulin dosing regimensللاطلاع

Multiple injection regimens (intensive insulin
therapy) are popular, with short-acting insulin being
taken before each meal, and intermediate- or long-acting insulin being injected once or twice daily (basal-bolus regimen).
This type of regimen allows greater freedom with regard to meal timing and more variable day-today
physical activity.
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Side-effects of insulin therapy

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Alternative insulin therapiesللاطلاع

‘Open-loop’ systems are battery-powered portable
pumps providing continuous subcutaneous (CSII),
intraperitoneal or intravenous infusion of insulin.
Artificial Pancreas uses glucose sensors to
communicate wirelessly with the insulin pump, which
would automatically adjust its rate.
Alternative routes of insulin delivery have been
investigated. Clinical trials with intrapulmonary (inhalation), transdermal and oral insulins are ongoing but as yet none has proven commercially viable.
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Whole pancreas transplantation
Transplantation of isolated pancreatic islets
Stem cells
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Diabetic ketoacidosis

A medical emergency and remains a serious cause of morbidity, principally in people with type 1 diabetes.
Mortality is low in the UK (approximately 2%) but remains high in developing countries and among non-hospitalised patients.
Mortality in DKA is most commonly caused in children
and adolescents by cerebral oedema and in adults by
hypokalaemia, acute respiratory distress syndrome and
comorbid conditions such as acute myocardial infarction,
sepsis or pneumonia.
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DKA is characteristic of type 1 diabetes and is often the presenting problem in newly diagnosed patients.
DKA may be precipitated by an intercurrent illness because of failure to increase insulin
dose appropriately to compensate for the stress response.
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للاطلاع

The hyperglycaemia causes a profound osmotic diuresis leading to dehydration and electrolyte loss, particularly of sodium and potassium.
Potassium loss is exacerbated by secondary hyperaldosteronism as a result of reduced renal perfusion.
Ketosis results from insulin deficiency, exacerbated by elevated catecholamines and other stress hormones, leading to unrestrained Lipolysis and supply of FFAs for hepatic ketogenesis.
When this exceeds the capacity to metabolise acidic ketones, these accumulate in blood. The resulting metabolic acidosis forces hydrogen ions into cells, displacing potassium ions.
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للاطلاع
• hyperketonaemia (≥ 3 mmol/L) and ketonuria
(more than 2+ on standard urine sticks)
• hyperglycaemia (blood glucose ≥ 11 mmol/L
(~200 mg/dL))
• metabolic acidosis (venous bicarbonate
< 15 mmol/L and/or venous pH < 7.3).
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للاطلاع

Every patient in DKA is potassium-depleted, but the
plasma concentration of potassium gives very little indication of the total body deficit.
Plasma potassium may even be raised initially due to disproportionate loss of water, catabolism of protein and glycogen, and displacement
of potassium from the intracellular compartment
by H+ ions.
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Clinical features of diabetic ketoacidosis

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Hypoglycaemia
Hypoglycaemia (blood glucose < 3.5 mmol/L (63 mg/dL)) in diabetes results in most circumstances from insulin therapy, less frequently from use of oral insulin secretagogues such as sulphonylurea drugs, and rarely with other anti-diabetic drugs.
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للاطلاع

In health, If blood glucose falls, endogenous insulin release from pancreatic B cells is suppressed; release of glucagon from pancreatic α cells is increased; and the autonomic
nervous system is activated, with release of catecholamines
both systemically and within the tissues.
In addition, stress hormones, such as cortisol and growth
hormone, are increased in the blood. These actions
reduce whole-body glucose uptake and increase hepatic
glucose production, maintaining a glucose supply to the
brain.
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للاطلاع

People with type 1 diabetes cannot regulate
insulin once it is injected subcutaneously, and so it continues to act, despite developing hypoglycaemia.
In addition, within 5 years of diagnosis, most patients will
have lost their ability to release glucagon specifically
during hypoglycaemia. This is thought to result mainly
from loss of α-cell regulation by β cells. These two
primary defects mean that hypoglycaemia occurs much
more frequently in people with type 1 and longer duration type 2 diabetes.
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Most common symptoms of hypoglycaemia
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Causes of hypoglycaemia

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Risk factors for severe hypoglycaemia

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Nocturnal hypoglycaemia in patients with type 1

diabetes is common but often undetected, as hypoglycaemia does not usually waken a person from sleep.
Patients may describe poor quality of sleep, morning headaches and vivid dreams or nightmares, or a partner may observe profuse sweating, restlessness, twitching or even seizures.
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للاطلاع

Exercise-induced hypoglycaemia occurs in people with well-controlled, insulin-treated diabetes because of hyperinsulinaemia. Suppression of endogenous insulin secretion to allow increased hepatic glucose production to meet the increased metabolic demand is
key to the normal physiological response to exercise.
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Emergency treatment of hypoglycaemiaللاطلاع

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COMPLICATIONS OF DIABETES
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Preventing diabetes complications

Glycaemic control
Control of other risk factors
Management of blood pressure
Management of dyslipidaemia
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Association between HbA1c and risk of diabetes complicationsللاطلاع

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