By Dr Sangeet Chadha

© 2004, John Walsh, P.A., C.D.E.

Before InsulinBefore Insulin

Before insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset

JL on 12/15/22 and 2 mos later

HISTORY

In 1869, a German medical student, Paul Langerhans, noted that the pancreas contains two distinct groups of cells the acinar cells, which secrete digestive enzymes, and cells that are clustered in islands, or islets, which he suggested served a second function. •

In the early 1900s, Gurg Zuelzer, an internist in Berlin, attempted to treat a dying diabetic patient with extracts of pancreas. Although the patient improved temporarily, he sank back into a coma and died when the supply of extract was exhausted.

Frederick Banting, a young Canadian surgeon, convinced J.J.R. Macleod, a professor of physiology in Toronto, to allow him access to a laboratory to search for the antidiabetic principle of the pancreas.

•Banting assumed that the islets secreted insulin but that the hormone was destroyed by proteolytic digestion prior to or during extraction. Together with Charles Best, a fourth-year medical student, he attempted to overcome the problem by ligating the pancreatic ducts. The acinar tissue degenerated, leaving the islets undisturbed; the remaining tissue then was extracted with ethanol and acid.

© 2004, John Walsh, P.A., C.D.E.

In Jan, 1922, Banting and Best injected a 14-year-old "charity” patient who weighed 64 lb with 7.5 ml of a "thick brown muck"in each buttock

Abscesses developed and he became more acutely ill

However, his blood glucose had dropped enough to continue refining what was called "iletin” insulin

6 weeks later, a refined extract caused his blood glucose to fall from 520 to 120 mg/dL in 24 hours

Leonard lived a relatively healthy life for 13 years before dying of pneumonia (no Rx then) at 27

•The Nobel Prize in medicine and physiology was awarded

to Banting and Macleod with remarkable rapidity in 1923,

and a furor over credit followed immediately.

Banting announced that he would share his prize with Best;

Macleod did the same with Collip.

© 2004, John Walsh, P.A., C.D.E.

Insulin Insulin Production Production

BeginsBegins First produced as “Connaught” by the Univ of Toronto

On May 30, 1922, Eli Lilly signed an agreement to pay royalties to the University to increase production

First bottles contained U-10 insulin

3 to 5 cc were injected at a time

Pain and abscesses were common until purer U-40 insulin became available

© 2004, John Walsh, P.A., C.D.E.

Impact Of Insulin On. Impact Of Insulin On. Life Life

Expectancy By The 1940’s Expectancy By The 1940’s Age at start of diabetes

50 30 10

Avg. age of death in 1897

58.0 34.1 11.3

Avg. age of death in 1945

65.9 60.5 45.0

Years Gained 8 26 34

In the post-absorptive period of a normal individual, low basal levels of circulating insulin are maintained through constant β 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:

depends 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 hypoglycemic 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.

Insulin secretion is regulated by glucose levels, certain amino acids, hormones and autonomic mediators.

Secretion is most commonly elicited by elevated glucose levels;.

The influx of Ca+2 results in a pulsatile secretion of insulin;

continued Ca+2 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.

Cell Types 

Alpha (A) cell

Beta (B) cell

Delta (D) cell

G cell

F cell (PP cell)1

Approximate Percent of Islet Mass 

20 %

75 %

3–5 %

1 %

1 %

Secretory Products 

Glucagon, proglucagon

Insulin, C-peptide, proinsulin, amylin

Somatostatin

Gastrin

Pancreatic polypeptide (PP)

Pancreatic Islet Cells and Their Secretory Products.

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 β-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.

Human insulin consists of 51 AA in two chains connected by 2 disulfide bridges

T1/2 ~5-10 minutes, degraded by glutathione-insulin transhydrogenase (insulinase) which cleaves the disulfide links.

Bovine insulin differs by 3 AAs, pork insulin differs by 1 AA.

Insulin is stored in a complex with Zn+2 ions.

Synthesis & release of insulin is modulated by:

1. Glucose (most important), AAs, FAs & ketone bodies stimulate release.

2. Glucagon & somatostation inhibit releases

3. α-Adrenergic stimulation inhibits release (most important).

4. β-Adrenergic stimulation promotes release.

5. Elevated intracellular Ca+2 promotes release.

Insulin binds to specific high affinity membrane receptors with tyrosine kinase activity

Phosphorylation cascade results in translocation of GLUT-4 (and some Glut-1) transport proteins into the plasma membrane.

It induces the transcription of several genes resulting in increased glucose catabolism & inhibits the transcription of genes involved in gluconeogenesis

. Insulin promotes the uptake of K+

into cells.

Insulin preparations

Regular insulin: Short acting, soluble, crystalline zinc insulin is

usually given subcutaneously; it rapidly lowers glucose levels.

All regular insulin is now made using genetically engineered bacteria, cow & pig no longer used.

onset 0.5-1.0 hrs peak 2- 4 hrs duration 5- 7hrs

Insulin lispro.

at positions B28 and B29, the sequence of the two residues has been reversed to match the sequence in IGF-1, which does not self-associate.

Like regular insulin, lispro exists as a hexamer in commercially available formulations.

Unlike regular insulin, lispro dissociates into monomers almost instantaneously following injection. Results in the characteristic rapid absorption and shorter duration of action compared with regular insulin.

Advantages. First, the prevalence of hypoglycemia is reduced by 20% to 30% ; second, glucose control, as assessed by hemoglobin A1c, is modestly but significantly improved (0.3% to 0.5%) with lispro as compared with regular insulin.

Insulin Aspart

Formed by the replacement of proline at B28 with aspartic acid. This reduces self-association to that observed with lispro.

Like lispro, insulin aspart dissociates rapidly into monomers following injection. Comparison of a single subcutaneous dose of aspart and lispro in a group of type 1 DM patients revealed similar plasma insulin profiles.

In clinical trials, insulin aspart and insulin lispro have had similar effects on glucose control and hypoglycemia frequency, with lower rates of nocturnal hypoglycemia as compared with regular insulin

Insulin Glulysine

In this compound, glutamic acid replaces lysine at B29, and lysine replaces asparagine at B23.

Similar to the other two available rapid-acting analogs, this causes a reduction in self-association and rapid dissociation into active monomers.

The time-action profile of insulin glulysine is similar to that of insulin aspart and lispro.

Similar to insulin aspart, glulysine has been approved by the Food and Drug Administration (FDA) for continuous subcutaneous insulin infusion (CSII) pump use.

Owing to their rapid onset, the fast-acting insulin analogs all may be injected immediately before or after a meal, which may confer considerable clinical advantages.

Many individuals with diabetes consume smaller amounts of food than originally planned. This, in the presence of a previously injected dose of insulin that was based on a larger meal, could result in postprandial hypoglycemia.Thus, in patients who have gastroparesis or loss of appetite, injection of a rapid-acting analog postprandially, based on the amount of food actually consumed, may provide smoother glycemic control.

1. Lente insulin:

Amorphous precipitate of insulin with zinc ion combined with 70% ultralente insulin. Onset is slower but more sustained than regular insulin. It cannot be given IV

( this has not been produced since 2005).

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 its effectiveness. It is usually given in combination with regular insulin.

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.

3. Detemir insulin: has a FA complexed with insulin resulting in slow dissolution.

Insulin Glargine

Two arginine residues are added to the C terminus of the B chain, and an asparagine molecule in position A21 on the A chain is replaced with glycine.

Glargine is a clear solution with a pH of 4.0. This pH stabilizes the insulin hexamer and results in a prolonged and predictable absorption from subcutaneous tissues.

Owing to acidic pH, it cannot be mixed with currently available short-acting insulin preparations (i.e., regular insulin, aspart, or lispro) that are formulated at a neutral pH.

In clinical studies, insulin glargine results in less hypoglycemia, has a sustained "peakless" absorption profile, and provides a better once-daily 24-hour insulin coverage than ultralente or NPH insulin.

May be administered at any time during the day with equivalent efficacy and no difference in the frequency of hypoglycemic episodes. Glargine does not accumulate after several injections.. Can be combined with various oral antihyperglycemic agents to effectively lower plasma glucose levels.

Use of a long-acting basal insulin alone will not control postprandial glucose elevations in insulin-deficient type 1 or type 2 DM.

Unlike traditional insulin preparations that are absorbed more rapidly from the abdomen than from the arm or leg, the site of administration does not influence the time-action profile of Glargine. Similarly, exercise does not influence Glargine's unique absorption kinetics, even when the insulin is injected into a working limb.

Insulin Detemir

Insulin detemir (deh-TEE-meer) has a fatty-acid side chain.

The addition of the fatty-acid side chain enhances association to albumin.

Slow dissociation from albumin results in long-acting properties similar to those of insulin glargine.

Name Type Onset(1) Peak(1) Duration(1)

Lispro Rapid 5-15 minutes30-75

minutes2-3 hours

Glulisine Rapid 5-15 minutes30-75

minutes2-4 hours

Aspart Rapid10-20

minutes1-3 hours 3-5 hours

Regular (R) Short-Acting 30 minutes 2-5 hours 5-8 hours

NPH (N) Intermediate 1-3 hours 6-12 hours 16-24 hours

Lente (L) Intermediate 1-3 hours 6-12 hours 16-24 hours

Ultralente (U) Long-Acting 3-5 hours 8-14 hours 18 hours

Glargine Lantus

Very Long-Acting

1 hourEvenly for 24

hours24-28 hours

NPH & Regular Mixed in either

50/50 mix, or70/30 mix

Premixed30-60

minutes2-12 hours

up to 18 hours

Mixtures of Insulins

Because intermediate-acting NPH insulins require several hours to reach adequate therapeutic levels, their use in diabetic patients usually requires supplements of rapid- or short-acting insulin before meals.

For convenience, these are often mixed together in the same syringe before injection. Insulin lispro, aspart, and glulisine can be acutely mixed (ie, just before injection) with NPH insulin without affecting their rapid absorption.

However, premixed preparations have thus far been unstable. To remedy this, intermediate insulins composed of isophane complexes of protamine with insulin lispro and insulin aspart have been developed.

These intermediate insulins have been designated as "NPL" (neutral protamine lispro) and "NPA" (neutral protamine aspart) and have the same duration of action as NPH insulin.

The FDA has approved 50%/50% and 75%/25% NPL/insulin lispro and 70%/30% NPA/insulin aspart premixed formulations. Additional ratios are available abroad.

Insulin glargine and detemir must be given as separate injections. They are not miscible acutely or in a premixed preparation with any other insulin formulation.

10/90

20/80

30/70

40/60

50/50

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ran

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Pre-mixed insulin

Daily Requirements.

Insulin production by a normal, thin, healthy person is between 18 and 40 units/day or about 0.2 to 0.5 units/kg of body weight per day

About half this amount is secreted in the basal state and about half in response to meals. Thus, basal secretion is about 0.5 to 1 units/h; after an oral glucose load, insulin secretion may increase to 6 units/h.

In non-diabetic, obese, and insulin-resistant individuals, insulin secretion may be increased fourfold or more. Insulin is secreted into the portal circulation, and about 50% is destroyed by the liver before reaching the systemic circulation

In a mixed population of type 1 DM patients, the average dose of insulin is usually 0.6 to 0.7 units/kg body weight per day.

Obese patients generally require more (about 2 units/kg per day) because of resistance of peripheral tissues to insulin.

Patients who require less insulin than 0.5 units/kg per day may have some endogenous production of insulin or may be more sensitive to the hormone because of good physical conditioning.

37

Insulin action

The action of insulin is to:

Help movement of glucose into the cells. Stimulate cells to take up glucose from

the blood. Increase the storage of glucose, amino

acids and fatty acids. Increase glycogen formation and storage

in the liver.

Liver Muscle Adipose↓ glucose production ↑ Glucose transport ↑ glucose transport

↑ glycolysis ↑ glycolysis ↑ lipogenesis& lipoprotein lipase activity

↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis

↑ Protein synthesis ↑ protein synthesis

39

Insulin administration

Sites: abdomen (preferable) & rotate site with each injection.

Timing: depends on the type of insulin.

Storage: unopened stored in refrigerator. Insulin in use, in cool, dark place <25º (not in fridge).

Expiry: use within 28 days of opening. Discard after expiry date.

Supply: prescription only.

1. Hypoglycemia-

2. Hypokalemia: insulin draws K+ into the cell with glucose (hyperglycemia with normal K+).

3. Anaphylaxis: when sensitized to non-human insulin gets non-human insulin (now rare).

4. Lipodystrophy at injection site

5. Weight gain

HypoglycemiaCommonly result from inadequate carbohydrate consumption, unusual physical exertion, and too large a dose of insulin.

Manifested by signs of autonomic hyperactivity—both sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger)—and may progress to convulsions and coma if untreated.

"hypoglycemic unawareness." When patients lack the early warning signs of low blood glucose. In patients with persistent, untreated hypoglycemia, the manifestations of insulin excess may develop—confusion, weakness, bizarre behavior, coma, seizures—at which point they may not be able to procure or safely swallow glucose-containing foods. Hypoglycemic awareness may be restored by preventing frequent hypoglycemic episodes.

An identification bracelet, necklace, or card in the wallet or purse, as well as some form of rapidly absorbed glucose, should be carried by every diabetic who is receiving hypoglycemic drug therapy.

Treatment of Hypoglycemia

Glucose administration. To expedite absorption, simple sugar or glucose should be given, preferably in liquid form. In mild hypoglycemia in a patient who is conscious and able to swallow, dextrose tablets, glucose gel, or any sugar-containing beverage or food may be given.

If more severe hypoglycemia has produced unconsciousness or stupor, the treatment of choice is to give 20–50 mL of 50% glucose solution by I.V infusion over a period of 2–3 minutes.

If I.V therapy is not available, 1 mg of Glucagon injected either S.C or I.M may restore consciousness within 15 minutes to permit ingestion of sugar.

If the patient is stuporous and glucagon is not available, small amounts of honey or syrup can be inserted into the buccal pouch. In general, however, oral feeding is contraindicated in unconscious patients.

Emergency medical services should be called immediately for all episodes of severely impaired consciousness.

Immunopathology of Insulin Therapy

There are two major types of immune disorders in these patients:

Insulin Allergy-

Insulin allergy, an immediate type hypersensitivity, is a rare condition in which local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies. In severe cases, anaphylaxis results. Because sensitivity is often to noninsulin protein contaminants, the human and analog insulins have markedly reduced the incidence of insulin allergy, especially local reactions.

Immune Insulin Resistance-

A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a negligible extent develops in most insulin-treated patients. Rarely, the titer of insulin antibodies leads to insulin resistance

Lipodystrophy at Injection Sites

Injection of animal insulin preparations sometimes led to atrophy of subcutaneous fatty tissue at the site of injection.

This type of immune complication is almost never seen ever since the development of human and analog insulin preparations of neutral pH. Injection of these newer preparations directly into the atrophic area often results in restoration of normal contours.

Hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the same site. However, this may be corrected by avoiding the specific injection site or by liposuction.

Unitage.

For therapeutic purposes, doses and concentrations of insulin are expressed in units. This tradition dates to the time when preparations of the hormone were impure, and it was necessary to standardize them by bioassay.

One unit of insulin is equal to the amount required to reduce the concentration of blood glucose in a fasting rabbit to 45 mg/dl (2.5 mM).

The current international standard is a mixture of bovine and porcine insulins and contains 24 units/mg. Homogeneous preparations of human insulin contain between 25 and 30 units/mg.

Almost all commercial preparations of insulin are supplied in solution or suspension at a concentration of 100 units/ml, which is about 3.6 mg insulin per milliliter (0.6 mM).

Insulin also is available in a more concentrated solution (500 units/ml) for patients who are resistant to the hormone.

Insulin delivery devices

1. Insulin syringes

2. External insulin pumps

3. Implantable insulin pumps

4. Insulin pens

5. Insulin jet injectors

6. Insulin inhalers

Insulin syringes

Insulin syringes are to be used with 10ml insulin vials

Syringes are manufactured in 30 unit (0.3ml), 50 unit (0.5ml) and 100 unit (1.0ml) measures. Its size will depend on the insulin dose, for example, it is easier to measure a 10 unit dose in a 30 unit syringe, and 55 units in a 100 unit syringe

Needles of the syringes are available in different lengths ranging from 8mm to 13mm. You will be informed by your doctor for its selection

Use each syringe only once.

Insulin Pumps

The insulin pump is a device that holds a reservoir of insulin. The pump is programmed to deliver insulin into the body through thin plastic tubing known as the infusion set

The pump is worn outside the body, in a pouch or on your belt. The infusion set has a fine needle or flexible cannula that is inserted just below the skin (usually on the abdomen) where it stays in place for two to three days

Only short or rapid acting insulin can be used in the pump. Whenever food is eaten, the pump is programmed to deliver a surge of insulin into the body similar to the way the pancreas does in people without diabetes. Between meals, a small and steady rate of insulin is released

Pump Evolution

1970s1970s 1980s1980s

Pump Evolution

Modern Day Insulin PumpsModern Day Insulin Pumps

Insulin Used In Pumps

Rapid-Acting Analogs are PreferredAspart (Novolog)Lispro (HumalogGlulisine (Apidra)

Modes of DeliveryBasalBolus

Basal Insulin

Steady “Drip” of Insulin

Matches Glucose Released by Liver

Meets Body’s Basic Energy Needs

May Need Different Settings at Different Times of Day

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Bolus Insulin

Given to “cover” carbs in meals and snacks.

Used to “correct” high blood glucose levels

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Insulin Infusion(aka “getting under your skin”)

Durable, clog-resistant tubing carries insulin from the pump to the infusion set*.

The infusion set delivers insulin into the fatty layer below the skin.

Set uses either a flexible plastic catheter (canula) or a steel needle.

Almost always disconnectable near the infusion site.

* OmniPod does not have * OmniPod does not have tubing; it attaches directly to tubing; it attaches directly to the skin.the skin.

Infusion Set Types

Infusion sets vary by:Angle of insertionCanula lengthPlastic vs. steelTubing length

Reduction in HbA1c1

Less BG Variability2

Reduction in duration, frequency and severity of hypoglycemia3

Better psychosocial outcomes & quality of life4

Practical Benefits of Pump Basal Delivery:

Stable BG between meals & overnight

Can skip/delay meals without dropping

Can vary sleep & work schedules

Fewer issues with travel/time zone changes

Can correct for dawn effect

No long-acting insulins (more consistent insulin action)

Immediate, temporary basal adjustments possible

Potential Drawbacks to Pump Therapy

Cost

Learning Curve

Extra Testing

Risk of Ketosis & DKA

Skin Irritation

Inconvenience

Time/Discomfort of Set Changes

Teaching & Follow-Up Required

Strategies for Success: DKA PreventionStrategies for Success: DKA Prevention

Unexplained High Blood Sugar

Check for Ketones

Ketones Ketones Negative Positive

Bolus w/Pump BS Doesn’t Drop 1. Shot w/Syringe

BS Drops 2. Drink Water 3. Change Out Pump

O.K.

Insulin Pens

‘Pen’ is available in all shapes and sizes. An insulin cartridge (3ml, containing 300 units of insulin) fits into the device. When finished, a new cartridge is inserted. However, some pen devices are pre-filled with insulin and the whole device is disposable

Durable pen available are NovoPen 3, NovoPen Demi, Innovo and HumaPen

Pre-filled disposable devices include Innolet, FlexPen and Novolet

Types of Insulin Pens

Rapid Acting Insulin Novolog FlexPen: Prefilled 300 units Humalog KwikPen: Prefilled 300 units Apidra SoloStar Pen: Prefilled 300 units (new April ’09) Humalog Memoir Pen: 300 unit cartridge Humalog Luxura Pen: 300 unit cartridge, can be dosed in

½ units

Basal Insulin Lantus SoloStar Pen: prefilled 300 units

Opticlick pen phasing out Levemir FlexPen : prefilled 300 units

Many mixed Insulins and older insulins also come in pens

Pros/Cons to Insulin pens

Advantages Easy to dial up

dose Can “count” clicks Kept at room

temperature Portable More discrete Memoir Pen: good

for patients with multiple care givers, able to identify last dose administered

Disadvantages Only 300 units Pens look similar,

rapid acting and basal could get mixed up

Difficult to “plunge”

Hold needle in for 5 seconds to ensure administration

Insulin Jet Injectors

Insulin jet injectors are high-pressure air devices that deliver a thin spray of insulin through and under the skin without any perforation.

This method is not a first class option, since it may not be extremely accurate, in terms of dose strength but it can be used, if the patient is terrified with the idea of a needle.

Insulin Inhalers

Insulin inhaler for insulin delivery by the pulmonary route. The patient presses the actuator to release the insulin from the aerosol container, in the manner similar to the administration of bronchodilators for the asthmatics.

The hormone is provided as a spray or a dry powder.

When inhaled, insulin enters the blood stream through the basic anatomic lung elements, called alveoli. Eg-Exubera .

www.diabetesclinic.ca 67

Non-diabetic Insulin Non-diabetic Insulin and Glucose Profilesand Glucose Profiles

9.0

6.0

3.0

07 8 9 101112 1 2 3 4 5 6 7 8 9

Insulin

Glucose

a.m. p.m.

Breakfast Lunch Supper75

50

25

0 Basal insulin

Basal glucose

Insulin(µU/mL)

Glucose(mmo/L)

Time of Day

Insulin Preparations & TreatmentVarious types of insulin are characterized by their

onset and duration of action

Examples of three regimens that provide both prandial and basal-insulin replacement. B = breakfast; L = lunch; S = supper

Insulin RegimensINTENSIVE INSULIN THERAPY

Intensive insulin regimens are prescribed for almost everyone with type 1 diabetes as well as many with type 2 diabetes.

Generally, the total daily insulin requirement in units is equal to the weight in pounds divided by four, or 0.55 times the person's weight in kilograms.

Approximately half the total daily insulin dose covers the background or basal insulin requirements, and the remainder covers meal and snack requirement and high blood sugar corrections. This is an approximate calculation and has to be individualized.

Increased insulin requirements typically occur with obesity, during adolescence, during the latter trimesters of pregnancy, and in individuals with type 2 diabetes.

This newer approach contrasts with conventional insulinotherapy. Rather than minimize the number of insulin injections per day (a technique which demands a rigid schedule for food and activities), the intensive approach favors flexible meal times with variable carbohydrate as well as flexible physical activities.

The trade-off is the increase from 2 or 3 injections per day to 4 or more injections per day, which was considered "intensive" relative to the older approach.

In North America in 2004, many endocrinologists prefer the term Flexible Insulin Therapy (FIT) to "intensive therapy" and use it to refer to any method of replacing insulin that attempts to mimic the pattern of small continuous basal insulin secretion of a working pancreas combined with larger insulin secretions at mealtimes. The semantic distinction reflects changing treatment.

Rationale for intensive or flexible treatment

Long-term studies like the UK Prospective Diabetes Study (UKPDS) and the Diabetes control and complications trial (DCCT) showed that intensive insulinotherapy achieved blood glucose levels closer to non-diabetic people and that this was associated with reduced frequency and severity of blood vessel damage. Damage to large and small blood vessels (macro- and microvascular disease) is central to the development of complications of diabetes mellitus.

This evidence convinced most physicians who specialize in diabetes care that an important goal of treatment is to make the biochemical profile of the diabetic patient (blood lipids, HbA1c, etc.) as close to the values of non-diabetic people as possible. This is especially true for young patients with many decades of life ahead.

A general description of intensive or flexible therapy

A working pancreas continually secretes small amounts of insulin into the blood to prevent the body from shifting into "starvation metabolism." This insulin is referred to as basal insulin secretion.

Most insulin used each day is produced during the digestion of meals. Insulin levels rise immediately as we begin to eat, remaining higher than the basal rate for 1 to 4 hours. This meal-associated (prandial) insulin production is roughly proportional to the amount of carbohydrate in the meal.

Intensive or flexible therapy involves supplying a continual supply of insulin to serve as the basal insulin, supplying meal insulin in doses proportional to nutritional load of the meals, and supplying extra insulin when needed to correct high glucose levels. These three components of the insulin regimen are commonly referred to as basal insulin, meal insulin, and high correction.

Advantages and disadvantages of intensive/flexible insulin therapy

The two primary advantages of intensive/flexible therapy over more traditional two or three injection regimens are:

greater flexibility of meal times, carbohydrate quantities, and physical activities, andbetter glycemic control to reduce the incidence and severity of the complications of diabetes.

Major disadvantages of intensive/flexible therapy are that it requires greater amounts of education and effort to achieve the goals, and it substantially increases the daily cost of diabetes care.

It is a common misconception that more frequent hypoglycemia is a disadvantage of intensive/flexible regimens. The frequency of hypoglycemia increases with increasing effort to achieve normal blood glucoses with any insulin regimen. When traditional regimens are used aggressively enough to achieve near-normal glycosylated hemoglobin A1c levels, hypoglycemia is at least as frequent as with flexible regimens. When used correctly, flexible regimens offer greater ability to achieve good glycemic control with easier accommodation to variations of eating and physical activity.

CONVENTIONAL INSULIN THERAPY

Conventional insulin therapy is usually prescribed only for certain people with type 2 diabetes who are felt not to benefit from intensive glucose control.

The insulin regimen ranges from one injection per day to many injections per day, using intermediate- or long-acting insulin alone or with short- or rapid-acting insulin or premixed insulins.

Referred to as sliding-scale regimens, conventional insulin regimens customarily fix the dose of the intermediate- or long-acting insulin, but vary the short- or rapid-acting insulin based on the plasma glucose level before the injection.

It is a 'conventional' therapy in which a mixture of short and long acting insulin is given in the morning and then again before the evening meal. Insulin is either drawn up from different bottles into the same syringe or use the pre-mixed insulin (disposable pen injectors). One plus point of this regimen is that there is no need of insulin shot at lunch and dinner time, but it becomes very essential to maintain timings of each meal. And, delaying or skipping of any meal will be oblivious cause of hypoglycemia. Lack of flexibility is again a problem if, a pre-mixed insulin is used as it is harder to vary the insulin dose according to the changes in your daily routine. The doses of short and long acting insulin cannot be varied independently of one another.

This regimen works as follow:

the morning short acting insulin takes care of breakfastthe morning long acting insulin takes care of lunch

the evening short acting insulin takes care of the evening mealthe evening long acting insulin takes care of overnight insulin needs

This older method (prior to the development home blood glucose monitoring) is still in use in a proportion of cases.

Conventional insulin therapy has these characteristics:

Insulin injections of a mixture of rapid and intermediate acting insulin are performed two or three times daily.

Meals are scheduled to match the anticipated peaks in the insulin profiles.

The target range for blood glucose levels is higher than is desired in the intensive regimen.

Frequent measurements of blood glucose levels were not used.The down side of this method is that it is difficult to achieve as good results of glycemic control as with intensive insulinotherapy. The advantage is that, for diabetics with a regular lifestyle, the regime is less intrusive than the intensive therapy.

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0

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Cause:

Counter regulatory hormones response to hypoglycemia at mid-night.

Increase in hepatic glucose production.

Insulin resistance because of the Counter regulatory hormones.

Treatment:

Decrease pre-supper intermediate insulin.

Defer the dose to 9 PM.

Change or start pre-bed snack.

Somogyi Phenomenon

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10

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Cause:

Less insulin at bed time.

More food at bed time.

Not using NPH at night.

Treatment:

Use enough dose.

Reduce bed time snack.

Add NPH pre-supper.

Dawn Phenomenon

Novo Nordisk announced on December 7, 2009, that it had initiated its first phase 1 trial with oral insulin analogue (NN1952).

Results from the trial, which is planned to enroll about 80 people, are expected to be reported in the first half of 2011.

Oral insulin

A Connecticut-based biopharmaceutical company called Biodel, Inc. is developing what it calls VIAtab, an oral formulation of insulin designed to be administered sublingually.

This therapy is a tablet that dissolves in minutes when placed under the tongue. In a Phase I study, VIAtab delivered insulin to the blood stream quickly and resembled the first-phase insulin release spike found in healthy individuals.

Biocon, Asia's largest biopharmaceutical company, based in Bangalore, India, is also developing an oral insulin product. It has recently entered phase III trials; the company hopes to launch their product, IN-105, in 2011.[29]

Pancreatic transplantation

Islet transplants had been highly experimental (read 'prone to failure') for many years, but some researchers in Alberta, Canada, have developed techniques with a high initial success rate . Nearly half of those who got an islet cell transplant were insulin-free one year after the operation; by the end of the second year that number drops to about one in seven.

However, researchers at the University of Illinois at Chicago (UIC) have slightly modified the Edmonton Protocol procedure for islet cell transplantation and achieved insulin independence in diabetes patients with fewer but better-functioning pancreatic islet cells.

Beta cell transplant may become practical in the near future. Additionally, some researchers have explored the possibility of transplanting genetically engineered non-beta cells to secrete insulin.

Oscillations

Insulin release from pancreas oscillates with a period of 3–6 minutes.

This is thought to avoid downregulation of insulin receptors in target cells and to assist the liver in extracting insulin from the blood.

This oscillation is important to consider when administering insulin-stimulating medication, since it is the oscillating blood concentration of insulin release, which should, ideally, be achieved, not a constant high concentration. This may be achieved by delivering insulin rhythmically to the portal vein or by islet cell transplantation to the liver. Future insulin pumps hope to address this characteristic.

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