The endocrine portion of the pancreas is comprised of the Islets of Langerhans, which contains at least 4 distinct cell types.  Each of the cells is responsible for the secretion of different hormones.  The alpha cells synthesise and secrete glucagon; beta cells -- insulin; delta cells -- somatostatin; and phi cells -- pancreatic polypeptide, which is thought to be used to aid digestion.

Type I -- Insulin Dependent DM (IDDM) -- In this condition, formerly known as juvenile onset diabetes, there is no circulating insulin and circulating levels of glucagon are typically high.  For some reason (as yet incompletely determined -- currently accepted theories include an auto-immune component) the beta cells do not respond to glucose to release insulin.  Therefore glucose is not utilised and the primary clinical sign is hyperglycæmia.  In response to this, fatty acids will be used as energy sources, creating a condition of ketoacidosis which may proceed to death.

Type II -- Non-Insulin Dependent DM (NIDDM) -- This condition usually occurs later in life (adult onset is the former name, although it may appear in young people).  There is a higher prevalence of NIDDM.  It is milder and may not require insulin (there is usually enough insulin circulating to prevent ketoacidosis but not enough to prevent the damage caused by hyperglycæmia or to be symptom-free).  In this form of DM, the tissues respond poorly to insulin.  Obesity is a common risk factor of NIDDM.

Liver
decrease glycogenolysis (inactivates enzymes responsible for breaking down glycogen)
decrease conversion of fatty acids and amino acids to ketoacids (similar mechanism)
increase glycogenesis (glucose storage as glycogen -- enzyme activation)
increase TG synthesis and VLDL formation (similar mechanism)
Muscle
increase amino acid uptake and protein synthesis
increase glucose transport into cell and glycogen synthesis for storage
Adipose
increase plasma lipoprotein lipase, freeing TG for uptake and storage in adipose
increase glucose uptake to esterify FA, to increase TG synthesis and storage

Benefits of Insulin Therapy in Diabetics -- In addition to the prevention of ketoacidosis, insulin therapy reduces the effects of chronic hyperglycæmia, including peripheral vascular disease, diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

Adverse Effects of Insulin

Hypoglycæmia -- An overdose of insulin, or alternately an insufficient intake of food, can result in a state of hypoglycæmia.  The specific effects are dependent upon whether the insulin was short or long acting.
Short acting insulin -- hypoglycæmia presents as enhanced sympathetic discharge -- tachycardia, palpitations, sweating, and tremors progressing to hunger, nausea, possible convulsions and coma.

Long acting insulin -- signs and symptoms of overdose include mental confusion and bizarre behaviour progressing to coma.

Note that many patients administer a combination of short and long acting insulins.  Therefore they may present with a combination of the above symptoms.

Treatment -- The patient should be given some form a sugar to correct the hypoglycæmia

Conscious -- administration may be as simple as candy, fruit juice et c., especially in mild hypoglycæmia.

Unconscious -- intravenous glucose (usually D50W) over 20 to 30 min or until the condition is corrected.  An alternate therapy, especially if the means of IV administration is not available is glucagon subcutaneously or intramuscularly (see below).

Semiconscious (or if glucagon is not available) -- short term measures may be taken by the placement of honey, syrup, or sugar in the buccal pouch.  Care should be taken that the sugar source is not aspirated.

Insulin Allergy -- as noted above, some patients may develop allergy to insulin.  If this occurs, substitution of a less allergenic source usually suffices. Since human recombinant has replaced animal sources of insulin, allergic reactions are of much less concern.

Insulin Resistance -- some patients may develop antibodies to insulin that do not result in anaphylactic reactions (as in allergy above) but do prevent the action of insulin at its receptor.  This is rare with the ultrapure insulins and practically unheard of with human insulin.  Substitution of one of these products will provide control in these patients.

Lipodystrophy -- Some patients experience changes in fat distribution near the injection site.  This is relatively rare now with the ultrapure and human forms of insulin.  It may present as fat atrophy (which usually reverses with substitution of the insulin type) or as fat hypertrophy (this may still occur with the ultrapure and human insulins) which may be minimised by alternating injection sites or treated with liposuction.

Mechanism of Action -- Glucagon acts at a specific receptor that is a typical seven transmembrane receptor coupled to a G protein.  Its second messenger is adenylyl cyclase/cAMP.

Pharmacodynamic Responses -- In general, the effects of glucagon are opposite those of insulin.
increase breakdown of stored glycogen (increase circulating levels of glucose)

increase gluconeogenesis, ketogenesis

glucagon also causes a secondary increase in insulin release (in response to the above effects) and adrenaline and noradrenaline release from the adrenal gland

glucagon exerts positive inotropic and positive chronotropic effects on the heart

glucagon will relax smooth muscle (especially GI smooth muscle) in a mechanism that is NOT cAMP mediated.

Severe hypoglycæmia (as noted above) -- IM, SC, or nasal administration

Beta antagonist toxicity -- the cardiac effects will reverse overdose effects of beta blockers (it is not used in emergent heart failure due to the endocrine effects)

Sulphonylureas -- These agents all work by the same mechanism(s) described below.  The primary differences in individual drugs are pharmacokinetic and adverse effects.

Mechanism of Action -- Three theories have been developed to support the action of these agents.
1) Blockade of the K channel, hastening beta-cell depolarisation and increasing insulin release.  This is probably the main effect of these agents.  The other theories, which may contribute to their action are

2) Decrease glucagon secretion (may be a secondary response to the increased insulin resulting from the above mechanism)

3) Potentiation of insulin's action at target cells (this may be a result of up-regulation subsequent to the lack of insulin in diabetes mellitus)

Pharmacodynamic Effects -- These agents increase the release of insulin from beta cells of the pancreas.  The other actions described above may contribute to their efficacy.

Adverse Effects -- All of these agents may cause a rash and GI upset, other effects are described below.   The primary side effect is the potential for hypoglycæmia, resulting either from overdose or inadequate food intake.

First Generation Agents

Tolbutamide -- its action may be prolonged by drugs that inhibit its metabolism (dicumarol, phenylbutazone, sulphonamides)

Chlorpropamide -- longest half-life, due to active metabolites, it may produce a disulfiram-like reaction, potential for hepatotoxicity with jaundice (all sulphonylureas possess this potential, it is greater with chlorpropamide), and also possesses ADH-like activity with water retention.

Tolazamide -- absorbed relatively slowly, postponing its action, ADH-like activity

Acetohexamide -- ADH-like activity

Second Generation Agents -- Typically are more potent than the 1st generation drugs -- glyburide, glipizide, glimepride, glyclozide
Glyburide also has mild ADH-like activity and may produce a mild disulfiram-like reaction
Miscellaneous Aspects of Sulphonylurea Therapy
Tolerance can develop to the effects of these drugs, this may be minimised by using the lowest effective dose.  Patients who develop tolerance may benefit from co-administration of low doses of insulin.

Mechanism of Action -- The exact mechanism of metformin is unknown.  It may act by one or more of the following proposed actions
1) increased glycolysis in tissue
2) decreased hepatic gluconeogenesis
3) decreased gastrointestinal absorption of glucose
4) decreased glucagon release
Pharmacodynamic Actions -- Metformin is effective in patients that do not have functioning beta cells.  It will reduce post-prandial glucose but does NOT reduce overnight, fasting glucose levels.  Hypoglycæmia resulting from drug action is rare.  For these reasons, metformin is better described as a "euglycæmic" rather than a hypoglycæmic drug.

Therapeutic Uses -- Metformin is used primarily in obese patients that are resistant to insulin therapy or as adjuncts to a sulphonylurea in patients who have developed tolerance to that drug.

Adverse Effects --

Gastrointestinal (20%) -- anorexia, nausea, vomiting, diarrhœa, discomfort.  Persistent diarrhœa in 2-3% of patients may require withdrawal of therapy.

Metformin may decrease vitamin B₁₂ absorption

Metformin may cause lactic acidosis, especially in patients with hypoxia, renal or hepatic insufficiency (its use in those patients is contraindicated).  Phenformin, another biguanide, was removed from the market in the late 1970s due to the high incidence of lactic acidosis.

Mechanism of Action -- These agents inhibit the enzyme alpha-glucosidase in the intestinal brush border.  This enzyme breaks down carbohydrates so that they may be absorbed.

Pharmacodynamic Effects -- Acarbose delays and decreases dietary carbohydrate absorption (reduces blood sugar).  Administration of acarbose will reduce post-prandial blood glucose levels by 30-50%.

Side Effects -- The primary side effect of acarbose is flatulence (20-30%) due to undigested carbohydrates.  It may also produce diarrhœa.  It decreases metformin absorption.

Mechanism of Action -- Troglitazone increases tissue sensitivity to insulin.  It is thought to do this by binding to and activating nuclear Peroxisome Proliferator Activated Receptors (PPAR) that regulate those genes responsible for utilisation of glucose and lipids.  It does not increase insulin release.

Pharmacodynamic Effects -- Troglitazone decreases the incidence of insulin resistance and will reduce insulin release in patients with functioning beta cells.  This is probably secondary to its ability to lower blood glucose by increasing its uptake into peripheral tissues.  It is currently thought that insulin resistance and hyperinsulinæmia may contribute to hypertension, hyperlipidæmia, and atherosclerosis.  Therefore, the use of troglitazone will be especially beneficial in those patients who have developed insulin resistance or who require high doses of insulin.

Therapeutic Use -- Troglitazone is used primarily in patients with insulin resistance, as an adjunct to other therapies, as noted below.

Adverse Reactions -- With the exception of potential hepatotoxicity, the thiazolidinediones are relatively side effect free.  Approximately 3% of patients taking troglitazone have exhibited elevated liver enzymes with levels of up to 30 times the normal upper limit.  In a few cases the hepatotoxicity has been irreversible and resulted in death due to liver failure or the necessity of liver transplant.  In cases where ALT elevations were mild, the hepatotoxicity appears to be reversible.  The mechanism of toxicity appears to be a standard idiosyncratic drug reaction that results in hepatocyte damage and necrosis.

Clinical Use -- Given the potential for life threatening hepatotoxicity, the FDA in conjuction with the manufacturer, has limited the approved uses of troglitazone to adjunct therapy in combination with a sulphonylurea and metformin in patients that do not exhibit optimal diabetic control.  Baseline ALT levels should be determined prior to initiation of troglitazone therapy and ALT levels should be drawn monthly for the first year of therapy and quarterly following the first year.

Drug Interactions -- Troglitazone has been shown to induce the cytochrome P450 3A4 isozyme.  This, in turn, has been shown to decrease circulating levels of oral contraceptives by as much as 30% (rendering them potentially ineffective as a contraceptive) and terfinadine by as much as 70%.  The absorption of troglitazone is reduced if it is co-administered with cholestyramine.

Chromium -- The trace element chromium is a necessary co-factor in glucose utilisation.  It has gained favour in the lay market for weight loss and diabetes.  It appears that in patients with normal levels of chromium is has no beneficial or therapeutic actions and additional chromium intake could lead to toxicity.  In patients with chromium deficiencies (which is relatively rare), supplementation is beneficial.

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