Definition:

1
Definition
Diabetes Mellitus

• Diabetes mellitus (DM) is a syndrome of chronic
  hyperglycemia due to relative insulin deficiency,
  resistance, or both.
• Epidemiology
• The prevalence of diabetes for all age groups
  worldwide was estimated to be 2.8 in 2000 and to
  increase to 4.4 in 2030.
• At diagnosis, 50 of patients have micro-vascular
  complications (diabetic neuropathy, nephropathy,
  or retinopathy).
• The risk of macro-vascular complications is at
  least two times higher than that of the general
  population.

• The risk of developing diabetes increases with
  age, obesity, and lack of physical activity.
• Type 2 diabetes is more common in individuals
  with a family history of the disease.
• It is more common in women with prior history of
  gestational diabetes and polycystic ovarian
  syndrome and in individuals with hypertension,
  dyslipidemia or impaired glucose tolerance.

Insulin structure and secretion

• Insulin is the key hormone involved in the
  storage and controlled release within the body of
  the chemical energy available from food.
• It is coded for on chromosome 11 and synthesized
  in the beta-cells of the pancreatic islets as a
  polypeptide hormone.
• After secretion, insulin enters the portal
  circulation and is carried to the liver, its
  prime target organ. About 50 of secreted insulin
  is extracted and degraded in the liver the
  residue is broken down by the kidneys. C-peptide
  is only partially extracted by the liver (and
  hence provides a useful index of the rate of
  insulin secretion).

• glucose metabolism
• Blood glucose levels are closely regulated in
  health within the range of 3.5-8.0 mmol/L (63-144
  mg/dL), despite the varying demands of food,
  fasting and exercise.
• The principal organ of glucose homeostasis is the
  liver, which absorbs and stores glucose (as
  glycogen) in the post-absorptive state and
  releases it into the circulation between meals to
  match the rate of glucose utilization by
  peripheral tissues.
• The liver by the process of gluconeogenesis can
  form new glucose from end metabolites of fat ,
  protein, and lactic acid.
• Glucose production
• About 200 g of glucose is produced and utilized
  each day. More than 90 is derived from liver
  glycogen and hepatic guconeogenesis, and the
  remainder from renal gluconeogenesis.

• Glucose utilization
• The brain is the major consumer of glucose. Its
  requirement is 1 mg/kg bodyweight per minute, or
  100 g daily in a 70 kg man.
• Glucose uptake by the brain is obligatory and is
  not dependent on insulin, and the glucose used is
  oxidized to carbon dioxide and water.
• Other tissues, such as muscle and fat, are
  facultative glucose consumers.
• Glucose taken up by muscle is stored as glycogen
  or broken down to lactate, which re-enters the
  circulation and becomes a major substrate for
  hepatic gluconeogenesis. But the main source of
  muscle energy is derived from fatty-acid
  oxidation.
• Fat tissue used glucose as a source of energy and
  as a substrate for triglyceride synthesis
  lipolysis releases fatty acids from triglyceride
  together with glycerol, another substrate for
  hepatic gluconeogenesis.

2
Principal actions of insulin

• Rapid (seconds)
• Increased transport of glucose, amino acids, and
  K into insulin-sensitive cells
• Intermediate (minutes)
• Stimulation of protein synthesis Inhibition of
  protein degradation
• Activation of glycolytic enzymes and glycogen
  synthetase
• Inhibition of phosphorylase and gluconeogenic
  enzymes
• Delayed (hours)
• Increase in mRNAs for lipogenic and other enzymes

• Hormonal regulation
• Insulin actions in the fasting and postprandial
  states differ . In the fasting state its main
  action is to regulate glucose release by the
  liver, and in the postprandial state it
  additionally facilitates glucose uptake by fat
  and muscle.
• The effect of counter-regulatory hormones
  (glucagon, epinephrine (adrenaline), cortisol and
  growth hormone) is to cause greater production of
  glucose from the liver and less utilization of
  glucose in fat and muscle for a given level of
  insulin.

• Glucose transport
• Cell membranes are not inherently permeable to
  glucose.
• A family of specialized glucose-transporter
  (GLUT) proteins carry glucose through the
  membrane into cells.
• These are glycoproteins, coded for on the short
  arm of chromosome 19.
• GLUT-1 - enables basal non-insulin-stimulated
  glucose uptake into many cells
• GLUT-2 - transports glucose into the beta-cell a
  prerequisite for glucose sensing.
• GLUT-3 - enables non-insulin-mediated glucose
  uptake into brain neurones and placenta.
• GLUT-4 - enables much of the peripheral action of
  insulin. It is the channel through which glucose
  is taken up into muscle and adipose tissue cells
  following stimulation of the insulin receptor .

Classification of DM

• DM is classified on the basis of the pathogenic
  process that leads to hyperglycemia.
• The two broad categories of DM are designated
• Type 1 (insulin-dependent diabetes mellitus)
• Type 2 (non-insulin-dependent diabetes mellitus)
• Type 1 diabetes is the result of complete or
  near-total insulin deficiency.
• Type 2 DM is a heterogeneous group of disorders
  characterized by variable degrees of insulin
  resistance, impaired insulin secretion, and
  increased glucose production.
• Type 2 DM is preceded by a period of abnormal
  glucose homeostasis classified as impaired
  fasting glucose (IFG) or impaired glucose
  tolerance (IGT).

3
Type 1 (insulin-dependent diabetes mellitus)
Secondary diabetes

• Although secondary diabetes accounts for only
  1-2 of all new cases at presentation, it should
  not be missed because the cause can often be
  treated
• Causes of secondary diabetes
• Pancreatic disease
• Cystic fibrosis
• Chronic pancreatitis
• Malnutrition-related pancreatic disease
• Pancreatectomy
• Hereditary haemochromatosis
• Carcinoma of the pancreas

• Endocrine disease
• Cushing's syndrome
• Acromegaly
• Thyrotoxicosis
• Phaeochromocytoma
• Glucagonoma
• Drug-induced disease
• Thiazide diuretics
• Corticosteroid therapy
• Insulin-receptor abnormalities
• Congenital lipodystrophy
• Acanthosis nigricans
• Genetic syndromes
• Friedreich's ataxia
• Dystrophia myotonica

• Causes
• Type 1 diabetes belongs to a family of
  HLA-associated immune-mediated organ-specific
  diseases.
• Autoantibodies directed against pancreatic islet
  constituents appear in the circulation within the
  first few years of life, prior to the clinical
  onset by many years , and also detected in cases
  of late onset auto- immune DM(LADA).
• Genetic susceptibility Type 1 diabetes is not
  genetically predetermined, but increased
  susceptibility to the disease may be inherited
  (polygenic).

• Inheritance
• The identical twin of a patient with type 1
  diabetes has a 30-50 chance of developing the
  disease, indicating that additional modifying
  factors are likely involved in determining
  whether diabetes develops.
• Children of people with type 1 diabetes have an
  increased chance of developing type 1 diabetes.
  by age 20 with a diabetic father the risk is
  (3-7),and with a diabetic mother is (2-3).
• If one child in a family has type 1 diabetes,
  each sibling has a 6 risk of developing
  diabetes by age 20.
• If siblings are HLA-identical (share the same
  HLA type as the affected child), the risk rises
  to about 20.

4
Environmental Factors

• Numerous environmental events have been proposed
  to trigger the autoimmune process in genetically
  susceptible individuals however, none have been
  conclusively linked to diabetes. Identification
  of an environmental trigger has been difficult
  because the event may precede the onset of DM by
  several years.
• Putative environmental triggers include viruses
  (coxsackie and rubella most prominently), bovine
  milk proteins, and nitrosourea compounds.

Prevention of Type 1 DM

• A number of interventions have successfully
  delayed or prevented diabetes in animal models.
• Though results in animal models are promising,
  these interventions have not been successful in
  preventing type 1 DM in humans. The Diabetes
  Prevention Trialtype 1 concluded that
  administering insulin (IV or PO) to individuals
  at high risk for developing type 1 DM did not
  prevent type 1 DM.
• In patients with new-onset type 1 diabetes,
  treatment with anti-CD3 monoclonal antibodies has
  recently been shown to slow the decline in
  C-peptide levels.

Type 2 (non-insulin-dependent diabetes
mellitus)

• Pathogenesis
• Hyperglycemia in type 2 diabetes likely results
  from complex genetic interactions, the expression
  of which modified by environmental factors such
  as body weight and exercise.
• Genetic factors
• type 2 diabetes shows a clear familial
  aggregation but does not inherited in a classic
  mendelian fashion.

• 2- Insulin resistance
• Type 2 diabetes is heterogeneous , both of the
  major pathogenic mechanisms i.e , impaired
  insulin secretion and impaired insulin
  action(insulin resistance or decreased insulin
  sensitivity)are operative in variable degrees in
  most patients.
• The mechanism of insulin resistance remains
  poorly understood there is a defect in insulin
  receptor, defects in more distal (post- receptor)
  pathways play a far greater role in insulin
  resistance .
• One important aspect of resistance is a reduced
  capacity for translocation of GLUT4 to cell
  surface in muscle cells, a separate defect in
  glycogen synthesis is also likely to be present
  and a variety of genetic abnormality in cellular
  transduction of the insulin signal.
• Hyperglycamia per se impairs the ß cell response
  to glucose and promotes insulin resistance.

• Abnormalities of insulin secretion manifest early
  in the course of type 2 diabetes. Normal subjects
  have a biphasic insulin response to intravenous
  glucose, but the first-phase insulin response is
  lost as hyperglycaemia develops, and insulin
  secretion in response to oral glucose is delayed
  and exaggerated.

5
CLINICAL PRESENTATION OF DIABETES

• Overview and prevention
• Whether an individual develops type 2 diabetes or
  not is largely due to genetic factors.
• When a person develops diabetes depends on
  lifestyle
• Clinical trials have shown that diet, exercise or
  agents such as metformin have a marked effect in
  delaying the onset of type 2 diabetes.

• Acute presentation
• Young people often present with a 2- to 6-week
  history and report the classic triad of symptoms
• polyuria - due to the osmotic diuresis that
  results when blood glucose levels exceed the
  renal threshold
• thirst - due to the resulting loss of fluid and
  electrolytes.
• weight loss - due to fluid depletion and the
  accelerated breakdown of fat and muscle secondary
  to insulin deficiency.
• Ketonuria is often present in young people(type
  1) and may progress to ketoacidosis if these
  early symptoms are not recognized and treated.

• Subacute presentation
• The clinical onset may be over several months or
  years, particularly in older patients. Thirst,
  polyuria and weight loss are typically present
  but patients may complain of such symptoms as
  easy fatigability , visual blurring (owing to
  glucose-induced changes in refraction), or
  pruritus vulvae or balanitis that is due to
  Candida infection.
• Complications as the presenting feature
• These include
• staphylococcal skin infections
• retinopathy noted during a visit to the optician
• a polyneuropathy causing tingling and numbness in
  the feet
• erectile dysfunction
• arterial disease, resulting in myocardial
  infarction or peripheral gangrene.

• Asymptomatic diabetes
• Glycosuria or a hyperglycemia may be detected on
  routine examination (e.g. for insurance purposes)
  in individuals who have no symptoms of
  ill-health.
• Glycosuria is not diagnostic of diabetes but
  indicates the need for further investigations.
• NB renal glycosuria is an inherited low renal
  threshold for glucose, transmitted either as a
  Mendelian dominant or recessive trait , with an
  incidence of about 1.
• Physical examination at diagnosis
• Evidence of weight loss and dehydration may be
  present, and the breath may smell of ketones.
• Older patients may present with established
  complications, and the presence of the
  characteristic retinopathy is diagnostic of
  diabetes.

6
Diagnosis
The spectrum of diabetes a comparison of type 1 and type 2 diabetes mellitus The spectrum of diabetes a comparison of type 1 and type 2 diabetes mellitus The spectrum of diabetes a comparison of type 1 and type 2 diabetes mellitus
Type 1 (insulin dependent) Type 2 (non-insulin dependent)
Epidemiology Younger (usually lt 30 years of age) Older (usually gt 30 years of age)
  Usually lean Often overweight
  Increased in those of Northern European ancestry All racial groups. Increased in peoples of Asian, African, Polynesian and American-Indian ancestry
  Seasonal incidence  
Heredity HLA-DR3 or DR4 in gt 90 No HLA links
  30-50 concordance in identical twins 50 concordance in identical twins
Pathogenesis Autoimmune disease No immune disturbance
    Islet cell autoantibodies Insulin resistance
    Insulitis  
    Association with other autoimmune diseases  
    Immunosuppression after diagnosis delays beta-cell destruction  
Clinical Insulin deficiency Partial insulin deficiency
  May develop ketoacidosis May develop hyperosmolar state
  Always need insulin Many come to need insulin when beta-cells fail over time
Biochemical Eventual disappearance of C-peptide C-peptide persists

• The National Diabetes Data Group and World Health
  Organization have issued diagnostic criteria for
  DM based on the following parameters (1) the
  spectrum of fasting plasma glucose (FPG) and the
  response to an oral glucose load (OGTToral
  glucose tolerance test) varies among normal
  individuals, and (2) DM is defined as the level
  of glycemia at which diabetes-specific
  complications occur rather than on deviations
  from a population-based mean. For example, the
  prevalence of retinopathy in Native Americans
  (Pima Indian population) begins to increase at a
  FPG gt 6.4 mmol/L (116 mg/dL).

7
Criteria for the Diagnosis of Diabetes Mellitus

• Symptoms of diabetes plus random blood glucose
  concentration 11.1 mmol/L (200 mg/dL) or
• Fasting plasma glucose 7.0 mmol/L (126 mg/dL)or
• Two-hour plasma glucose 11.1 mmol/L (200 mg/dL)
  during an oral glucose tolerance test.
• NB The glucose tolerance test is only required
  for borderline cases and for diagnosis of
  gestational diabetes.

The glucose tolerance test - WHO criteria
Adult 75 g glucose in 300 mL water. Child 1.75
g glucose/kg bodyweight. Only a fasting and a
120-min sample are needed. Results are for
venous plasma - whole blood values are lower. NB
FPG 5.66.9 mmol/L (100125 mg/dL) is defined
as IFG

Normal Impaired glucose tolerance Diabetes mellitus
Fasting Less than 7.0 mmol/L Less than 7.0 mmol/L More than 7.0 mmol/L (126mg/dL)
2 h after glucose Less than 7.8 mmol/L(140mg/dL) Between 7.8 and 11.0 mmol/L(140 and 199 mg/dL) 11.1 mmol/L or more (200mg/dL)

• Some investigators have advocated the hemoglobin
  A1C (A1C) as a diagnostic test for DM. Though
  there is a strong correlation between elevations
  in the plasma glucose and the A1C, the
  relationship between the FPG and the A1C in
  individuals with normal glucose tolerance or mild
  glucose intolerance is less clear, and thus the
  use of the A1C is not currently recommended to
  diagnose diabetes.
• The diagnosis of DM has profound implications for
  an individual from both a medical and financial
  standpoint. Thus, these diagnostic criteria must
  be satisfied before assigning the diagnosis of
  DM. Abnormalities on screening tests for diabetes
  should be repeated before making a definitive
  diagnosis of DM, unless acute metabolic
  derangements or a markedly elevated plasma
  glucose are present .
• The revised criteria also allow for the diagnosis
  of DM to be withdrawn in situations where the FPG
  reverts to normal.

TREATMENT OF DIABETES

• Goals of management
• Reduce acute and chronic complications.
• Improve quality of life.
• Prevent premature diabetes-related death.
• Maintain hemoglobin A1c less than 7.
• Clinical Standers
• FBG 100-120 mg\dl
• PPBG 140-160 mg\dl
• Bedtime BG 100-140mg\dl

8

• The role of patient education and community care
• The care of diabetes is based on self-management
  by the patient, who is helped and advised by
  those with specialized knowledge , as whatever
  the technical expertise applied, the outcome
  depends on willing cooperation by the patient.
• The best time to educate the patient is soon
  after diagnosis. Organized education programmes
  will involve all healthcare workers, including
  nurse specialists, dietitians and podiatrist.
• Lifestyle modifications
• Weight loss
• Exercise
• Dietary management

Nutritional Recommendations for Adults with
Diabetes

• Fat  
•  2035 of total caloric intake
•   Saturated fat lt 7 of total calories   
•  Two or more servings of fish/week provide -3
  polyunsaturated fatty acids  
• Carbohydrate  
•  4565 of total caloric intake (low-carbohydrate
  diets are not recommended) .
• Amount and type of carbohydrate important
• Sucrose-containing foods may be consumed with
  adjustments in insulin dose

• Protein
• 1035 of total caloric intake (high-protein
  diets are not recommended) i.e 1.0 to 1.5 g\kg
  per day, to be restricted in nephropathy 0.8 g\kg
  per day.
• Other components
• Fiber-containing foods may reduce postprandial
  glucose peak
• Non-nutrient sweeteners
• Exercise
• Exercise has multiple positive benefits including
  
• cardiovascular risk reduction,
• reduced blood pressure,
• maintenance of muscle mass
• reduction in body fat
• weight loss and lowering plasma glucose (during
  and following exercise) and increasing insulin
  sensitivity.

• In patients with diabetes, it is recommended to
  be150 min/week (distributed over at least 3 days)
  of aerobic physical activity.
• In patients with type 2 DM, the exercise regimen
  should also include resistance training.
• Pharmacotherapy
• Oral Hypoglycemic agents
• Sulphonylureas
• Their principal action is to promote insulin
  secretion in response to glucose
• Minor extra panceatic role as insulin sensitizers.

9
Properties of the most commonly used sulphonylureas Properties of the most commonly used sulphonylureas
Drug Features
Tolbutamide Lower maximal efficacy than other sulphonylureas
  Short half-life - preferable in elderly
  Largely metabolized by liver - can use in renal impairment
Glibenclamide, glipizide and glimepiride Long biological half-lifeActive metabolitesRenal excretion - avoid in renal impairment
Gliclazide Fairly long biological half-life
  Largely metabolized by liver - can use in renal impairment
  More costly
Properties of the most commonly used
sulphonylureas (cont.)
Drug Features
Chlorpropamide Very long biological half-life
  Renal excretion - avoid in renal impairment
  1-2 develop inappropriate ADH-like syndrome
  Facial flush with alcohol
Very inexpensive - major issue for developing countries
Drug interactions and side-effects

• Sulphonylureas should be used with care in
  patients with liver disease, and only those
  primarily excreted by the liver should be given
  to patients with renal impairment. (Tolbutamide
  ,Gliclazide)
• All encourage weight gain and are therefore not
  drugs of first choice in obese patients.
• Tolbutamide is the safest drug in the very
  elderly because of its short duration of action.
• Hypoglycaemia is the most common and dangerous
  side-effect. Specially in long acting type eg,
  Chlorpropamide
• Skin rashes and other sensitivity reactions do
  rarely occur.
• All sulphonylureas bind to circulating albumin
  and may be displaced by other drugs, such as
  sulphonamides, that compete for their binding
  sites ,also interact with warfarin.

10
Biguanides

• Metformin is currently the best validated primary
  treatment for type 2 diabetes.
• Mechanism of action
• It remains unclear but it reduces
  gluconeogenesis, thus suppressing hepatic glucose
  output, and it increases insulin sensitivity.
• Unlike the sulphonylureas it does not induce
  hypoglycaemia in normal volunteers.
• It is particularly helpful in the overweight
  since it does not promote weight gain.
• It may be given in combination with
  sulphonylureas or thiazolidinediones.
• Side-effects
• Anorexia, epigastric discomfort and diarrhoea.
• Lactic acidosis has occurred in patients with
  severe hepatic or renal disease, and metformin is
  contraindicated when these are present.
• Most diabetologists withdraw the drug when serum
  creatinine exceeds 1.5 in males and 1.4 in
  females.

Thiazolidinediones

• The thiazolidinediones (more conveniently known
  as the 'glitazones') reduce insulin resistance by
  interaction with peroxisome proliferator-activated
  receptor-gamma (PPAR-gamma), a nuclear receptor
  which regulates genes involved in lipid
  metabolism and insulin action.
• One suggestion is that they act indirectly via
  the glucose-fatty acid cycle, lowering free fatty
  acid levels and thus promoting glucose
  consumption by muscle.
• They can be used alone or in combination with
  other agents.
• The glitazones reduce hepatic glucose production,
  an effect that is synergistic with that of
  metformin, and also enhance peripheral glucose
  uptake thus, potentiate the effect of endogenous
  insulin.

• Side effects
• Contraindicated in mild liver impairment(
  elevated serum trasaminases 2.5 times the upper
  limit ofnormal).
• Given cautiously to patient with heart failure ,
  renal impairment.
• Fluid retention , mild oedema and weight gain.
• a-Glucosidase Inhibitors
• -Glucosidase inhibitors (acarbose and miglitol)
  reduce postprandial hyperglycemia by delaying
  glucose absorption they do not affect glucose
  utilization or insulin secretion .
• These drugs, taken just before each meal, reduce
  glucose absorption by inhibiting the enzyme that
  cleaves oligosaccharides into simple sugars in
  the intestinal lumen.

• Side effects
• GIT disturbance flatulence , abdominal
  distension .
• Contraindicated in hepatic impairment.
• Meglitinides
• Repaglinide and nateglinide are non-sulphonylurea
  insulin secretagogues known as the meglitinides.
• Advantages
• Low incideace of hypoglycaemia as they are
  short-acting agents that promote insulin
  secretion in response to meals .
• Disadvantages
• They are more expensive than standard
  sulphonylureas.

11
Insulin treatment

• Indications
• Type 1 (insulin-dependent diabetes mellitus)
• Gestational diabetes
• Diabetic ketoacidosis, hyperosmolar diabetic coma
• Hyperglycemia despite maximum doses of oral
  agents
• Surgical procedures
• Infection, acute injury, stress
• Allergy or other serious reaction to oral agents

• Insulin delivery methods
• Syringes
• Pens
• Insulin pump
• Inhalation

Pharmacokinetics of Insulin Preparations
Time of Action Time of Action Time of Action
Preparation Onset, h Peak, h Effective Duration, h
Short-acting, subcutaneous      
  Lispro lt0.25 0.51.5 34
  Aspart lt0.25 0.51.5 34
  Glulisine lt0.25 0.51.5 34
  Regular 0.51.0 23 46
Short-acting, inhaled      
  Inhaled regular insulin lt0.25 0.51.5 46
Preparation Onset, h Peak, h Effective Duration, h
Long-acting      
  NPH 14 610 1016
  Detemir 14   1220
  Glargine 14   24
Insulin Combinations      
  75/2575 protamine lispro, 25 lispro lt0.25 1.5 h  Up to 1016
  70/3070 protamine aspart, 30 aspart lt0.25 1.5 h  Up to 1016
  50/5050 protamine lispro, 50 lispro lt0.25 1.5 h  Up to 1016
  70/3070 NPH, 30 regular insulin 0.51 Dual 1016
  50/5050 NPH, 50 regular insulin 0.51 Dual 1016
12
Insulin administration patterns

• 1-Conventional One or two injections per day of
  intermediate acting such as zinc insulin
  (lente)or isophane(NPH) with or without the
  addition of small amount of regular insulin.
  Usual starting dose is 20 u\day.
• Premixed preparations may be used as two thirds
  of the dose before breakfast and one third before
  dinner.
• 2- Multiple S.C insulin injections intermediate
  , long acting or basal insulin single bedtime
  dose with regular insulin prior to each meal.
• 3- Continuous S.C insulin infusion insulin pump

Guide to adjusting insulin dosage according to blood glucose test results Guide to adjusting insulin dosage according to blood glucose test results Guide to adjusting insulin dosage according to blood glucose test results
Blood glucose persistently too high Blood glucose persistently too low
Before breakfast Increase evening long-acting insulin Reduce evening long-acting insulin
Before lunch Increase morning short-acting insulin Reduce morning short-acting insulin or increase mid-morning snack
Before evening meal Increase morning long-acting insulin or lunch short-acting insulin Reduce morning long-acting insulin or lunch short-acting insulin or increase mid-afternoon snack
Before bed Increase evening short-acting insulin Reduce evening short-acting insulin
Complications of insulin therapy

• At the injection site
• Shallow injections result in intradermal insulin
  delivery and painful, reddened lesions or even
  scarring.
• Injection site abscesses occur but are extremely
  rare.
• Local allergic responses sometimes occur early in
  therapy but usually resolve spontaneously.
• Generalized allergic responses are exceptionally
  rare.
• Fatty lumps, known as lipohypertrophy, may occur
  as the result of overuse of a single injection
  site with any type of insulin.
• Systemic complications
• Insulin resistance
• Hypoglycemia
• Weight gain ,especially if the insulin dose is
  increased inappropriately.

Monitoring the Level of Glycemic Control

• Self-Monitoring of Blood Glucose (SMBG) The
  frequency of SMBG measurements must be
  individualized and adapted to address the goals
  of diabetes care. Individuals with type 1 DM or
  individuals with type 2 DM taking multiple
  insulin injections each day should routinely
  measure their plasma glucose three or more times
  per day to estimate and select mealtime boluses
  of short-acting insulin and to modify long-acting
  insulin doses. Most individuals with type 2 DM
  require less frequent monitoring, though the
  optimal frequency of SMBG has not been clearly
  defined.
• Assessment of Long-Term Glycemic Control
• Glycated hemoglobin or A1C (standardized range
  4-6.5) should be measured in all individuals
  with DM during their initial evaluation and as
  part of their comprehensive diabetes care. As the
  primary predictor of long-term complications of
  DM, the A1C should mirror, to a certain extent,
  the short-term measurements of SMBG.
• It ideally to kept lt 7.

13
Acute Complications of DM

• Diabetic ketoacidosis
• Diabetic ketoacidosis (DKA) was formerly
  considered a hallmark of type 1 DM, but it can
  occur in obese individuals with type 2 DM with
  absolute or relative insulin deficiency.
• It is usually seen in the following
  circumstances
• previously undiagnosed diabetes
• interruption of insulin therapy
• the stress of intercurrent illness.
• Pathogenesis
• DKA results from relative or absolute insulin
  deficiency combined with counter regulatory
  hormone excess (glucagon, catecholamines,
  cortisol, and growth hormone).

• This promotes gluconeogenesis, glycogenolysis,
  and ketone body formation in the liver, as well
  as increases in substrate delivery from fat and
  muscle (free fatty acids, amino acids) to the
  liver.
• Rising glucose levels lead to an osmotic
  diuresis, loss of fluid and electrolytes, and
  dehydration.
• Plasma osmolality rises and renal perfusion
  falls. In parallel, rapid lipolysis occurs,
  leading to elevated circulating free fatty-acid
  levels.
• Accumulation of ketone bodies produces a
  metabolic acidosis. Vomiting leads to further
  loss of fluid and electrolytes.
• ketone bodies are excreted in the urine ,and also
  appear in the breath, producing a distinctive
  smell similar to that of acetone.
• Respiratory compensation for the acidosis leads
  to hyperventilation, 'air hunger'.
• Progressive dehydration impairs renal excretion
  of hydrogen ions and ketones, aggravating the
  acidosis.
• As the pH falls below 7.0 , pH-dependent enzyme
  systems in many cells function less effectively.
• Untreated, severe ketoacidosis is invariably
  fatal.

• Clinical Features
• Symptoms of DKA are of gradual onset , may take
  days .
• Hyperglycemia Polyuria, nocturia, polydipsia ,
  weight loss.
• Dehdration dry skin and tongue, hypotension,
  weak rapid pulse oliguria.
• Acidosis(ketone bodies )Vomiting ,abdominal pain
  , acetone odour in breath and Kussmaul breathing
  .
• Lethargy and central nervous system depression
  may evolve into coma with severe DKA but should
  also prompt evaluation for other reasons for
  altered mental status (infection, hypoxia, etc.).
  
• Cerebral edema, an extremely serious complication
  of DKA, is seen most frequently in children.
• Signs of infection, which may precipitate DKA,
  should be sought on physical examination, even in
  the absence of fever.
• Tissue ischemia (heart, brain) can also be a
  precipitating factor.

14
Management of Diabetic Ketoacidosis

• Confirm diagnosis (plasma glucose, positive serum
  ketones, metabolic acidosis).
• Admit to hospital intensive-care setting may be
  necessary for frequent monitoring or if pH lt 7.00
  or unconscious.
• Assess
• Serum electrolytes (K, Na, Mg2, Cl-,
  bicarbonate, phosphate)
• Acid-base statuspH, HCO3-, PCO2,
  ß-hydroxybutyrate
• Renal function (creatinine, urine output)
• Replace fluids 23 L of 0.9 saline over first
  13 h (1015 mL/kg per hour) subsequently, 0.45
  saline at 150300 mL/h change to 5 glucose and
  0.45 saline at 100200 mL/h when plasma glucose
  reaches 250 mg/dL (14 mmol/L).
• Administer short-acting insulin IV (0.1
  units/kg) or IM (0.3 units/kg), then 0.1 units/kg
  per hour by continuous IV infusion increase 2-
  to 3-fold if no response by 24 h. If initial
  serum potassium is lt 3.3 meq/L, do not administer
  insulin until the potassium is corrected to gt 3.3
  meq/L.
• Assess patient What precipitated the episode
  (noncompliance, infection, trauma, infarction)?
  Initiate appropriate workup for precipitating
  event (cultures, CXR, ECG).

• Measure capillary glucose every 12 h measure
  electrolytes (especially K, bicarbonate,
  phosphate) and anion gap every 4 h for first 24
  h.
• Monitor blood pressure, pulse, respirations,
  mental status, fluid intake and output every 14
  h.
• Replace K 10 meq/h when plasma K lt 5.5 meq/L,
  ECG normal, urine flow and normal creatinine
  documented administer 4080 meq/h when plasma K
  lt 3.5 meq/L or if bicarbonate is given.
• Continue above until patient is stable, glucose
  goal is 150250 mg/dL, and acidosis is resolved.
  Insulin infusion may be decreased to 0.050.1
  units/kg per hour.
• Administer intermediate or long-acting insulin as
  soon as patient is eating. Allow for overlap in
  insulin infusion and subcutaneous insulin
  injection.

Hyperglycemic Hyperosmolar Non-ketotic
state(HHNS)

• It is a metabolic emergency characteristic of
  old uncontrolled type 2 diabetes.
• Common precipitating factors include
• Consumption of glucose-rich fluids .
• Concurrent medication such as thiazide diuretics
  or steroids.
• Intercurrent illness.
• N.B Non-ketotic coma and ketoacidosis represent
  two ends of a spectrum rather than two distinct
  disorders

Pathogenesis

• Relative insulin deficiency and inadequate fluid
  intake are the underlying causes of HHS.
• Insulin deficiency increases hepatic glucose
  production (through glycogenolysis and
  gluconeogenesis) and impairs glucose utilization
  in skeletal muscle .
• Hyperglycemia induces an osmotic diuresis that
  leads to intravascular volume depletion, which is
  exacerbated by inadequate fluid replacement.
• The absence of ketosis in HHS is not completely
  understood. Presumably, the insulin deficiency is
  only relative and less severe than in DKA, lower
  levels of counter regulatory hormones and free
  fatty acids, and also may be because that the
  liver is less capable of ketone body synthesis or
  that the insulin/glucagon ratio does not favor
  ketogenesis.

15
Clinical Features

• dehydration and stupor or coma Impairment of
  consciousness is directly related to the degree
  of hyperosmolality.
• Evidence of underlying illness such as pneumonia
  or pyelonephritis may be present.
• The hyperosmolar state may predispose to stroke,
  myocardial infarction or arterial insufficiency
  in the lower limbs.
• Laboratory Abnormalities and Diagnosis
• Sever hyperglycemia plasma glucose may be gt55.5
  mmol/L (1000 mg/dL).
• Hyperosmolality (gt350 mosmol/L).
• Prerenal azotemia.
• In contrast to DKA, acidosis and ketonemia are
  absent or mild,but small anion gap metabolic
  acidosis may be present secondary to increased
  lactic acid.
• Moderate ketonuria, if present, is secondary to
  starvation.

• N.B
• The normal range of osmolality is 285-300
  mOsm/kg. It can be measured directly, or can be
  calculated approximately from the formula
  Osmolality 2(Na K) glucose urea
  (all in mmol/L).
• The normal anion gap is less than 17. It is
  calculated as (Na K) - (Cl- HCO3-).
• Treatment
• Fluid replacement should initially stabilize the
  hemodynamic status of the patient (13 L of 0.9
  normal saline over the first 23 h). the rapidity
  of reversal of the hyperosmolar state must
  balance the need for free water repletion with
  the risk that too rapid a reversal may worsen
  neurologic function.
• If the serum sodium gt 150 meq/L, 0.45 saline
  should be used. After hemodynamic stability is
  achieved, the IV fluid administration is directed
  at reversing the free water deficit using
  hypotonic fluids (0.45 saline initially then 5
  dextrose in water, D5W).

• The calculated free water deficit (which averages
  910 L) should be reversed over the next 12 days
  (infusion rates of 200300 mL/h of hypotonic
  solution)guided by CV line monitoring of the
  volume status.
• Insulin and K supplement are like DKA.
• Treatment of the underlying illness.
• Prognosis
• The reported mortality ranges as high as 20-30,
  mainly because of the advanced age of the
  patients and the frequency of intercurrent
  illness.

Lactic acidosis

• Lactic acidosis may occur in diabetic patients on
  biguanide therapy, if the therapeutic dose is
  exceeded or the drug is not withheld in patients
  with advanced hepatic or renal dysfunction.
• Patients present in severe metabolic acidosis
  with a large anion gap (normally less than 17
  mmol/L), usually without significant
  hyperglycaemia or ketosis.
• Treatment
• Rehydration and infusion of isotonic 1.26
  bicarbonate.
• Prognosis
• The mortality is in excess of 50.

16
Treatment
Hypoglycemia

• It occurs more common in type 1 DM especially
  those on intensive insulin therapy, but it is
  rare with the recent insulin analogues that have
  no high beaks as old insulin formula.
• Pathogenesis
• In normal subjects , fasting results in release
  of adrenaline and glucagon to stimulate
  glycogenolysis and gluconeogenesis .This hormone
  release is blunted in type 1 DM .
• NB
• If hypoglycemia occurs in type 2 DM on oral
  hypoglycemic agents ,it is more prolonged ,more
  sever ,so the pt should be hospitalized and
  monitored for at least 24 h after resolution of
  the attack.

• Predisposing factors
• Missed or small meal
• Over dose of insulin
• Unexpected increased activity.
• Clinical Features
• The most common symptoms and signs of
  hypoglycaemia are neurological as the brain
  consumes about 50 of the total glucose produced
  by the liver these include cold sweating
  ,shaking, tachycardia, dilated pupils and
  tremors.(release of adrenaline )
• If the condition is prolonged pt will develop
  cognitive impairment, dizziness, hunger,
  convulsions, coma without lateralizing signs and
  bilateral extensor planter response ,and
  irreversible brain damage death. (decrease
  glucose supply to the brain which is the only
  fuel)

Chronic Complications of DM

• If the pt is conscious a sugary fluid is given
  and a meal is taken after 15 minutes
• If the pt is unconscious IV glucose ( 25-50 ml
  50)
• Glucagon 1mg IM
• Searching for and correcting the predisposing
  factors

• The chronic complications of DM affect many organ
  systems and are responsible for the majority of
  morbidity and mortality associated with the
  disease these include
• Microvascular complications
• Retinopathy,(non proliferative/proliferative),
  macular edema
• Neuropathy sensory and motor(mono- and
  polyneuropathy), autonomic
• Nephropathy
• Macrovascular complications
•  Coronary artery disease
•   Peripheral arterial disease
•   Cerebrovascular disease

• Other complications
• Gastrointestinal (gastroparesis, diarrhea)
•  Genitourinary (uropathy/sexual dysfunction)  
•  Dermatologic infectious  
•  Cataracts
•   Glaucoma   
• Periodontal disease

17
Mechanisms of Complications

• Although chronic hyperglycemia is an important
  etiologic factor leading to complications of DM,
  the mechanism(s) by which it leads to such
  diverse cellular and organ dysfunction is
  unknown.
• Four prominent theories, have been proposed to
  explain how hyperglycemia might lead to the
  chronic complications of DM.
• One theory
• the increased intracellular glucose leads to the
  formation of advanced glycosylation end products
  (AGEs) via the nonenzymatic glycosylation of
  intra- and extracellular proteins. AGEs have been
  shown to cross-link proteins (e.g., collagen,
  extracellular matrix proteins), accelerate
  atherosclerosis, promote glomerular dysfunction,
  reduce nitric oxide synthesis, induce endothelial
  dysfunction, and alter extracellular matrix
  composition and structure.
• The serum level of AGEs correlates with the
  level of glycemia, and these products accumulate
  as glomerular filtration rate declines.

• A second theory
• It is based on the observation that hyperglycemia
  increases glucose metabolism via the sorbitol
  pathway by the enzyme aldose reductase. Increased
  sorbitol concentration increases cellular
  osmolality, generates reactive oxygen species,
  and likely leads to other types of cellular
  dysfunction. However, testing of this theory in
  humans, using aldose reductase inhibitors, has
  not demonstrated significant beneficial effects
  on clinical endpoints of retinopathy, neuropathy,
  or nephropathy.
• A third hypothesis proposes that hyperglycemia
  increases the formation of diacylglycerol leading
  to activation of protein kinase C (PKC). Among
  other actions, PKC alters the cellular membrane
  ,and plasma lipoproteins rendering them more
  atherogenic. endothelial cells and neurons.
  Inhibitors of PKC are being studied in clinical
  trials.

• A fourth theory proposes that hyperglycemia
  increases the flux through the hexosamine
  pathway. The hexosamine pathway may alter
  function by glycosylation of proteins such as
  endothelial nitric oxide synthase or by changes
  in gene expression of transforming growth factor
  (TGF-) or plasminogen activator inhibitor-1
  (PAI-1).
• Growth factors as appear to play an important
  role in DM-related complications, and their
  production is increased by most of these proposed
  pathways. Vascular endothelial growth factor A
  (VEGF-A) is increased locally in diabetic
  proliferative retinopathy. TGF- is increased in
  diabetic nephropathy and stimulates basement
  membrane production of collagen and fibronectin
  by mesangial cells. Other growth factors, such as
  platelet-derived growth factor, epidermal growth
  factor, insulin-like growth factor I, growth
  hormone, basic fibroblast growth factor, and even
  insulin, have been suggested to play a role in
  DM-related complications.

• A possible unifying mechanism is that
  hyperglycemia leads to increased production of
  reactive oxygen species or superoxide in the
  mitochondria these compounds may activate all
  four of the pathways described above. Although
  hyperglycemia serves as the initial trigger for
  complications of diabetes, it is still unknown
  whether the same pathophysiologic processes are
  operative in all complications or whether some
  pathways predominate in certain organs.

Ophthalmologic Complications of Diabetes Mellitus

• DM is the leading cause of blindness between the
  ages of 20 and 74 in the United
  States,individuals with DM are 25 times more
  likely to become legally blind than individuals
  without DM.
• Blindness is primarily the result of progressive
  diabetic retinopathy and clinically significant
  macular edema.
• Diabetic retinopathy is classified into two
  stages
• Nonproliferative diabetic retinopathy usually
  appears late in the first decade or early in the
  second decade of the disease and is marked by
  retinal vascular microaneurysms, blot
  hemorrhages, and cotton wool spots. Alterations
  in retinal blood flow, increased retinal vascular
  permeability and abnormal retinal
  microvasculature, all of which lead to retinal
  ischemia.
• Proliferative diabetic retinopathyThe
  appearance of neovascularization in response to
  retinal hypoxia is the hallmark of proliferative
  diabetic retinopathy

18
Diabetic nephropathy

• These newly formed vessels appear near the optic
  nerve and/or macula and rupture easily, leading
  to vitreous hemorrhage, fibrosis, and ultimately
  retinal detachment.
• Duration of DM and degree of glycemic control are
  the best predictors of the development of
  retinopathy hypertension is also a risk factor.
  Non proliferative retinopathy is found in almost
  all individuals who have had DM for gt20 years
  (25 incidence with 5 years, and 80 incidence
  with 15 years of type 1 DM).
• Treatment
• Early detection and treatment Annual
  ophthalmologic examinations should begin within
  5years in type1 and at the time of disease
  detection in type 2.
• Optimization of glycemic control delays and slows
  progression of non-proliferative retinopathy with
  only little evidence in proliferative retinopathy
  .
• Aggressive control of hypertension.
• Retinal LASER photocoagulation if progressive
  retinopathy threatens vision.
• Surgical treatmentVitrectomy in vitreous
  hemorrhage or to cut extensive fibrous bands
  causing retinal detachments.

• It is the leading cause of ESRD worldwide and a
  leading cause of DM-related morbidity and
  mortality.
• It is usually manifests 15-25 years after
  diagnosis and affects 25-35 of patients
  diagnosed under the age of 30 years.
• Pathophysiology
• The earliest functional abnormality in the
  diabetic kidney is renal hypertrophy associated
  with a raised glomerular filtration rate. This is
  related to poor glycaemic control.
• As the kidney becomes damaged by diabetes, the
  afferent arteriole becomes vasodilated to a
  greater extent than the efferent glomerular
  arteriole. This increases the intraglomerular
  filtration pressure, leads to further damaging
  the glomerular capillaries and increased shearing
  forces locally which are thought to contribute to
  mesangial cell hypertrophy and increased
  secretion of extracellular mesangial matrix
  material. This process eventually leads to
  glomerular sclerosis.

• Albuminuria At first 'microalbuminuria' -
  amounts of urinary albumin so small ,may be
  tested for by radioimmunoassay or by using
  special dipsticks.
• It is a predictive marker of progression to
  nephropathy in type 1 diabetes, and of increased
  cardiovascular risk in type 2 diabetes.
• progression to overt proteinuria (gt300 mg/d),
  only 50 of individuals progress to
  macroalbuminuria over the next 10 years.
• Once macroalbuminuria is present, there is a
  steady decline in GFR, and 50 of individuals
  reach ESRD in 710 years.
• Once macroalbuminuria develops, blood pressure
  rises slightly and the pathologic changes are
  likely irreversible.
• NB Some individuals with type 1 or type 2 DM
  have a decline in GFR in the absence of micro- or
  macroalbuminuria and this is the basis for
  assessing the GFR on an annual basis using serum
  creatinine.

• Ischaemic lesions
• Arteriolar lesions, with hypertrophy and
  hyalinization of the vessels, can occur in
  patients with diabetes. The appearances are
  similar to those of hypertensive disease and lead
  to ischaemic damage to the kidneys.
• Diagnosis
• 1-Urine albumin assay
• As the onset of diabetic nephropathy is often
  silent screening of younger patients for
  microalbuminuria has to be done routinely, since
  there is evidence that meticulous glycaemic
  control or early antihypertensive treatment at
  this stage may delay the onset of frank
  proteinuria.
• Once proteinuria is present, other possible
  causes for this should be considered ,also assay
  should be done in absence of urinary tract
  infection,DKA, and vigorous exercise.

19

• 2- Serum urea , Creatinine , Creatinine
  clearance.
• 3-Abdominal ultrasound to exclude obstractive
  nephropathy
• 4- Fundus examination in almost all cases of
  diabetic nephropathy ,diabetic retinopathy is
  present.
• Management
• Improved glycemic control reduces the rate at
  which microalbuminuria appears and progresses in
  type 1 and type 2 DM. However, once
  macroalbuminuria exists, it is unclear whether
  improved glycemic control will slow progression
  of renal disease. During the phase of declining
  renal function, insulin requirements may fall as
  the kidney is a site of insulin degradation.
  Furthermore, many glucose-lowering medications
  (sulfonylureas and metformin) are contraindicated
  in advanced renal insufficiency.
• Aggressive treatment of blood pressure with a
  target below 130/80 mmHg has been shown to slow
  the rate of deterioration of renal failure
  considerably. Angiotensin-converting enzyme
  inhibitors or an angiotensin receptor II
  antagonist are the drugs of choice.

• These drugs should also be used in normotensive
  patients with persistent microalbuminuria as
  reduction in albuminuria occurs with this
  treatment.
• Associated diabetic retinopathy tends to progress
  rapidly, and frequent ophthalmic supervision is
  essential.
• Management of ESRD is made more difficult by the
  fact that patients often have other complications
  of diabetes such as blindness, autonomic
  neuropathy or peripheral vascular disease.
  Vascular shunts tend to calcify rapidly and hence
  chronic ambulatory peritoneal dialysis may be
  preferable to haemodialysis.
• The failure rate of renal transplants is somewhat
  higher than in non-diabetic patients. A segmental
  pancreatic graft is sometimes performed at the
  same time as a renal graft .

Diabetic neuropathy

• It occurs in 50 of individuals with
  long-standing type 1 and type 2 DM. It may
  manifest as polyneuropathy, mononeuropathy,
  and/or autonomic neuropathy.
• As with other complications of DM, the
  development of neuropathy correlates with the
  duration of diabetes and glycemic control.
• Additional risk factors are
• BMI (the greater the BMI, the greater the risk
  of neuropathy) and smoking.
• The presence of cardiovascular disease,
  hypertension ,and elevated triglycerides.
• It is recommended to screen for distal symmetric
  neuropathy beginning with the initial diagnosis
  of diabetes and screen for autonomic neuropathy 5
  years after diagnosis of type 1 DM and at the
  time of diagnosis of type 2 DM.
• All individuals with diabetes should then be
  screened annually for both forms of neuropathy.

• Pathophysiology
• The earliest functional change in diabetic nerves
  is delayed nerve conduction velocity the
  earliest histological change is segmental
  demyelination, caused by damage to Schwann cells.
• In the early stages axons are preserved,
  implying prospects of recovery, but at a later
  stage irreversible axonal degeneration develops.
• The following varieties of neuropathy occur
• symmetrical mainly sensory polyneuropathy
  (distal)
• acute painful neuropathy
• mononeuropathy and mononeuritis multiplex
• (a) cranial nerve lesions
• (b) isolated peripheral nerve lesions
• diabetic amyotrophy
• autonomic neuropathy.

20

• Symmetrical mainly sensory polyneuropathy
• It is the most common form of diabetic
  neuropathy.
• It most frequently presents with distal sensory
  loss (deep before superficial), but up to 50 of
  patients do not have symptoms of neuropathy.
• Hyperesthesia and paresthesia also may occur.
• As neuropathy progresses any combination of these
  symptoms may develop including a sensation of
  numbness, tingling, sharpness, or burning that
  begins in the feet and spreads proximally.
• Involvement of the hands is much less common and
  results in a 'stocking and glove' sensory loss.
• Complications include unrecognized trauma,
  beginning as blistering due to an ill-fitting
  shoe, and leading to ulceration.

• Diabetic polyradiculopathy is a syndrome
  characterized by severe disabling pain in the
  distribution of one or more nerve roots.
• It may be accompanied by motor weakness.
• Intercostal or truncal radiculopathy causes pain
  over the thorax or abdomen. Involvement of the
  lumbar plexus or femoral nerve may cause severe
  pain in the thigh or hip and may be associated
  with muscle weakness in the hip flexors or
  extensors (diabetic amyotrophy).
• Fortunately, diabetic polyradiculopathies are
  usually self-limited and resolve over 612
  months.
• Mononeuropathy (dysfunction of isolated cranial
  or peripheral nerves) is less common than
  polyneuropathy in DM and presents with pain and
  motor weakness in the distribution of a single
  nerve.
• A vascular etiology has been suggested, but the
  pathogenesis is unknown.
• Involvement of the third cranial nerve is most
  common and is heralded by diplopia. Sometimes
  other cranial nerves IV, VI, or VII (Bell's
  palsy) are affected. Peripheral mononeuropathies
  or simultaneous involvement of more than one
  nerve (mononeuropathy multiplex) may also occur.

• Acute painful neuropathy A diffuse, painful
  neuropathy is less common. The patient describes
  burning or crawling pains in the feet, shins and
  anterior thighs. These symptoms are typically
  worse at night, and pressure from bedclothes may
  be intolerable.
• It may present at diagnosis or develop after
  sudden improvement in glycaemic control (e.g.
  when insulin is started). It usually remits
  spontaneously after 3-12 months if good control
  is maintained.
• A more chronic form, developing later in the
  course of the disease, is sometimes resistant to
  almost all forms of therapy.
• Neurological assessment is difficult because of
  the hyperaesthesia experienced by the patient.

• Autonomic neuropathy
• Asymptomatic autonomic disturbances can be
  demonstrated on laboratory testing in many
  patients, but symptomatic autonomic neuropathy is
  rare.
• It affects both the sympathetic and
  parasympathetic nervous systems.
• The cardiovascular system
• Vagal neuropathy results in tachycardia at rest
  ,loss of sinus arrhythmia,loss of cardiovascular
  reflexes such as the Valsalva maneuver are
  impaired , postural hypotension occurs owing to
  loss of sympathetic tone to peripheral arterioles
  , and warm foot with a bounding pulse as a result
  of peripheral vasodilatation.
• Gastrointestinal tract Vagal damage can lead to
  
• gastroparesis, often asymptomatic, but sometimes
  leading to intractable vomiting.
• Autonomic diarrhoea often occurs at night
  accompanied by urgency and incontinence.
• Diarrhoea and steatorrhoea may occur owing to
  small bowel bacterial overgrowth treatment is
  with antibiotics such as tetracycline.
• Constipation is the most commen symptom, but
  diarrhoea is the most distressing.
• Urinary bladder involvement Loss of tone,
  incomplete emptying, and stasis (predisposing to
  infection) resulting in an atonic, painless,
  distended bladder.

21

• Male erectile dysfunction
• Erectile dysfunction in diabetes has many causes
  including anxiety, depression, alcohol excess,
  drugs, primary or secondary gonadal failure,
  hypothyroidism, and inadequate vascular supply
  owing to atheroma in pudendal arteries.
• The history and examination should focus on these
  possible causes. Blood is taken for LH, FSH,
  testosterone, prolactin and thyroid function.
• Skin and sweat glands
• Distal anhydrosis ,gustatory sweating
  ,compensatory truncal and facial sweating

• Treatment
• Treatment of diabetic neuropathy is less than
  satisfactory
• Improved glycemic control should be aggressively
  done and will improve nerve conduction velocity,
  but symptoms of diabetic neuropathy may not
  necessarily improve.
• Risk factors for neuropathy such as hypertension
  and hypertriglyceridemia should be treated.
• Chronic, painful diabetic neuropathy is difficult
  to treat but may respond to antidepressants or
  anticonvulsants .
• Aldose reductase inhibitors do not offer
  significant symptomatic relief.
• Since the pain of acute diabetic neuropathy may
  resolve over time, medications may be
  discontinued as progressive neuronal damage from
  DM occurs.
• For gastroparisis agents with some efficacy
  include dopamine agonists metoclopramide, and
  domperidone before each meal.
• Erythromycin interacts with the motilin receptor
  and may promote gastric emptying. Treatment of
  bacterial overgrowth with antibiotics is
  sometimes useful .
• Diabetic diarrhea in the absence of bacterial
  overgrowth is treated symptomatically.

• Diabetic cystopathy should be treated with timed
  voiding or self-catheterization, possibly with
  the addition of bethanechol.
• Drugs that inhibit type 5 phosphodiesterase are
  effective for erectile dysfunction, but their
  efficacy in individuals with DM is slightly lower
  than in the nondiabetic population .
• Sexual dysfunction in women may be improved with
  use of vaginal lubricants, treatment of vaginal
  infections, and systemic or local estrogen
  replacement.