October 22, 1797 The first parachutist

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October 22, 1797The first parachutist

• AndrÉ-Jacques Garnerin attached the parachute to
  a hydrogen balloon and ascended to an altitude of
  3,200 feet above Paris. He then clambered into
  the basket and severed the parachute from the
  balloon. As he failed to include an air vent at
  the top of the prototype, Garnerin oscillated
  wildly in his descent, but he landed shaken but
  unhurt half a mile from the balloon's takeoff
  site. In 1799, Garnerin's wife, Jeanne-Genevieve,
  became the first female parachutist. In 1802,
  Garnerin made a spectacular jump from 8,000 feet
  during an exhibition in England. He died in a
  balloon accident in 1823 while preparing to test
  a new parachute.

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Insulin Oral Hypoglycemics

• The peptide hormones directly involved in
  responding to and controlling blood glucose
  levels are located in the islets of Langerhans in
  the pancreas insulin is secreted by ß-cells and
  glucagon by a2 cells. Diabetes is a disorder of
  inadequate insulin activity it is associated with
  episodes of both hyper- and hypo-glycemia. It is
  the episodes of hyperglycemia that are associated
  with long-term complications.

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Long term complications
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Diabetes Mellitus

• The incidence of diabetes is increasing at am
  alarming rate in the US.

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• Diabetes is a heterogeneous group of syndromes
  characterized by the elevation of glucose levels
  due to a relative or absolute deficiency of
  insulin frequently inadequate insulin release is
  complicated by excess glucagon release.

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Diabetes can be divided into two main types

• Type I Insulin dependent diabetes mellitus,
  there is an absolute deficiency of insulin this
  is most often diagnosed in the peripubertal
  period. Type I is associated with massive ß-cell
  necrosis usually ascribed to an autoimmune
  mechanism possibly associated with viral
  infection or toxin exposure.
• Type II Non-insulin dependent diabetes mellitus,
  a relative deficiency of insulin function. The
  disorder is influenced by genetic factors, aging,
  obesity and peripheral insulin resistance. The
  metabolic perturbations are not as dramatic as in
  type I but the long term complications associated
  with repetitive hyperglycemic episodes are the
  same.

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• The long term complications of diabetes may be
  divided into two large groups
• 1. Macrovascular These complications are
  associated with pathology of the large medium
  sized vessels this includes CHD, stroke, PVD
• 2. Microvascular These complications are due to
  vascular pathology of the small vessels and
  include neuropathy, nephropathy, retinopathy

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Normal Glucose Control

• In the post-absorptive period of a normal
  individual, low basal levels of circulating
  insulin are maintained through constant ß cell
  secretion. This suppresses lipolysis,
  proteolysis and glycogenolysis. After ingesting
  a meal a burst of insulin secretion occurs in
  response to elevated glucose and amino acid
  levels. When glucose levels return to basal
  levels, insulin secretion returns to its basal
  level.
• Type I DM Lack of functional ß-cells prevents
  mitigation of elevated glucose levels and
  associated insulin responses. The onset and
  progression of neuropathy, nephropathy and
  retinopathy are directly related to episodic
  hyperglycemia.
• Type II DM The pancreas retains some ß-cell
  function but effective insulin response is
  inadequate for the glucose level. Actual insulin
  levels may be normal or supra-normal but it is
  ineffective (insulin resistance).

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Treatment

• Type I Type 1s depend on exogenous insulin to
  prevent hyperglycemia and avoid ketoacidosis.
  The goal of type 1 therapy is to mimic both the
  basal and reactive secretion of insulin in
  response to glucose levels avoiding both hyper-
  and hypo-glycemic episodes.
• Type II The goal of treatment is to maintain
  glucose concentrations within normal limits to
  prevent long term complications. Weight
  reduction, exercise (independent of weight
  reduction) and dietary modification decrease
  insulin resistance and are essential steps in a
  treatment regimen. For many this is inadequate
  to normalize glucose levels, the addition of
  hypoglycemic agents is often required, often
  insulin therapy is required.

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Insulin secretion

• Insulin secretion is regulated by glucose levels,
  certain amino acids, hormones and autonomic
  mediators.
• Secretion is most commonly elicited by elevated
  glucose levels increased glucose levels in
  ß-cells results in increased ATP levels, this
  results in a block of K channels causing
  membrane depolarization which opens Ca2
  channels.
• The influx of Ca2 results in a pulsatile
  secretion of insulin continued Ca2 influx
  results in activation of transcription factors
  for insulin.
• Oral glucose elicits more insulin secretion than
  IV glucose oral administration elicits gut
  hormones which augment the insulin response.
• Insulin is normally catabolized by insulinase
  produced by the kidney.

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Mechanism of Insulin Release in the Pancreas
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INSULIN

• Insulin is a peptide hormone synthesized as a
  precursor (pro-insulin) which undergoes
  proteolytic cleavage to form a dipeptide the
  cleaved polypeptide remnant is termed protein C.
  
• Both are secreted from the ß-cell, normal
  individuals secrete both insulin and (but much
  less) pro-insulin.
• Type 2s are found to secrete high levels of
  pro-insulin (pro-insulin is inactive) measuring
  the level of C-protein is a more accurate
  estimation of normal insulin secretion in type 2s.

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Sources of Insulin

• Human insulin has largely replaced beef/pork
  insulin. This is produced using genetically
  engineered e. coli or yeast.
• Slight modification in insulin AA sequence yields
  agents with different pharmacokinetic properties
  lispro, aspart glulisine have faster onset of
  action and shorter duration of effect.
• Insulin glargine insulin detimir are longer
  acting than normal insulin.
• The onset duration of action of various insulin
  preparations is related to their ability to form
  multimeric complexes/crystals the more complex
  the aggregates the slower and more prolonged the
  effect.

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• Insulin Preparations Treatment
• Various types of insulin are characterized by
  their onset and duration of action

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The Goal of Insulin Therapy
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Insulin administration

• Being a peptide the administration of Insulin is
  generally limited the parenteral delivery,
  usually subcutaneously it can be given
  intravenously when needed.
• Delivery via a variable constant infusion pump is
  possible but this requires frequent testing of
  blood sugar and manipulation of the delivery rate
  following meals.
• An aerosol form of insulin was expected to ease
  management of glucose levels however inhalation
  was associated with a significant inflammatory
  response in the lung and testing has been halted.

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• Adverse Reactions
• The most serious complication with insulin is
  hypoglycemia. The counter regulatory hormones
  (glucagon, epinephrine, growth hormone and
  cortisol) are often abnormal in diabetics and
  ineffective in combating excess exogenous
  insulin. Occasionally some recipients of
  slightly modified insulins develop allergic
  reactions.

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Rapid onset ultrashort-acting preparations

• Regular insulin short acting, soluble,
  crystalline zinc insulin is usually given
  subcutaneously it rapidly lowers glucose levels.
• Lispro, Aspart Glulisine preparations are
  classified as ultrashort acting forms with onset
  more rapid than regular insulin and a shorter
  duration. These are less often associated with
  hypoglycemia. Lispro insulin is given 15 minutes
  prior to a meal and has its peak effect 30-90
  minutes after injection (vs. 50-120 minutes for
  regular insulin).
• Glulisine can be given anywhere from 15 minutes
  prior to 20 minutes after beginning a meal.
• Administration of insulins are arranged to mimic
  the normal basal, prandial post-prandial
  secretion of insulin. Short acting forms are
  usually combined with longer acting preparations
  to achieve this.

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Intermediate acting Insulin Preparations

• 1. Lente insulin This is a amorphous
  precipitate of insulin with zinc ion combined
  with 70 untralente insulin. Onset is slower but
  more sustained than regular insulin. It cannot
  be given IV.
• 2. Isophane NPH insulin Neutral protamine
  Hagedorn insulin is a suspension of crystalline
  zinc insulin combined with protamine (a
  polypeptide). The conjugation with protamine
  delays its onset of action and prolongs it
  effectiveness. It is usually given in
  combination with regular insulin.

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Prolonged-acting insulin preparations

• 1.Ultralente a suspension of zinc insulin
  forming large particles which dissolve slowly,
  delaying onset and prolonging duration of action.
• 2.Insulin glargine Precipitation at the
  injection site extends the duration of action of
  this preparation.

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• Insulin Combinations
• Various premixed combinations of various
  preparations of insulin are available to ease
  administration. Standard combination use should
  follow establishment of an acceptable regime of
  individual preparations.

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Standard Vs. Intensive Treatment
The trade off between standard intensive
therapy is more frequent hypoglycemic events
(hypoglycemic events, seizures and coma) for a
marked delay in the onset of diabetic
complications both microvascular
macrovascular. HbA1c Hemoglobin A1c is a useful
measure of glucose control over the prior 3-6
months, hyperglycemic episodes result in the
nonspecific glycosylation of various
proteins. See fig 24-9.
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