Chapter 29:  Management of Diabetes

Physiology

• Human Endocrine pancreas: one million islets of Langerhans: four hormone producing cells:

• Left- anti-insulin, Right- anti-glucagon; Ó 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

• insulin: anabolic/storage hormone
• islet amyloid polypeptide (IAPP): unknown function
• glucagon: hypoglycemic factor used for glycogen storage mobilization
• pancreatic peptide: facilitates digestion

"Inputs to beta cells and effects of insulin, including negative feedback on glucose and amino-acids levels. "

courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

• Diabetes mellitus-- most important disease involving endocrine pancreas:

  • Major manifestations:

    1. inappropriate hyperglycemia

    2. metabolic disorders

  • Two types:

    • Type I diabetes -- insulin-dependent diabetes mellitus (IDDM)

    • Type II diabetes -- non-insulin dependent diabetes mellitus (NIDDM)

  • Properties of Type I diabetes:

    • severe form; associated with ketosis (when untreated)

    • usually juvenile in onset (occasionally adult onset)

    • Catabolic disorder:

      • insulin nearly absent

      • plasma glucagon elevated

      • pancreatic B cell: not responsive to insulinogenic stimuli

      • exogenous insulin required to:

        1. prevent ketosis

        2. reduce hyperglucagonemia

        3. reverse catabolic state

    • Possible causes:

      •  infectious etiology-- genetic predisposition

      •  toxic environmental factor-- genetic predisposition

        • autoimmune response against pancreatic B cell antigens

      •  Pancreatic B cell functional damage:

        • mumps virus

        • coxsackievirus B4

        • destructive cytotoxins and antibodies from sensitized immunocytes

        • Autoimmune component suggested given that pancreatic B cell damage is reduced when immunosuppressive drugs {cyclosporine/azathioprine} are mastered early Type I diabetes.

          • Pancreatic tissue transplanted from a nondiabetic monozygotic twins into the diabetic twin is rapidly destroyed (in absence of immunosuppression)

      • Autoimmune Mechanism:

        • Immune system mediation of pancreatic beta cell obstruction (Type I diabetes)

          • Associated with other autoimmune endocrinopathies

            1. adrenal-insufficiency

            2. Hashimoto's thyroiditis

          • Most patients have antibodies against insulin and other beta cell antigen

      • Pancreatic beta cell destruction -- development of insulin-dependent diabetes mellitus:

        • slow loss of insulin reserve

        • Prediabetic stages:

          1. Islet cell tumor on a development (normal glucose; normal glucose tolerance; normal insulin response to glucose load)

          2. Decreased glucose tolerance (fasting blood glucose: normal; last prediabetic phase)

          3. Fasting hyperglycemia (no ketosis, even with poorly control diabetes)-- looks like NIDDM

          4. Insulin-dependent stage -- ketoacidosis occurs, especially following stress (in this point life-long insulin therapy is required or pancreatic transplant)

      •  Immune-directed pancreatic beta cell destruction:

        • humoral and cell-mediated processes (cell-mediated mechanisms more important)

        • Islet cell antibodies: -- antibodies against:

          1. insulin

          2. proinsulin

          3. glutamic acid decarboxylase (two forms)

          4. ganglioside ganglioside antigens

        • Immune cell involvement:

          1. activated cytotoxic T lymphocytes (CD8+)

          2. macrophages

          3. releases cytokines (interleukin 1, tumor necrosis factor alpha {TNF-alpha}

        • With appearance of overt diabetes: most insulin-producing cells have been destroyed

• Overview of clinical presentation: Type I diabetes:

  • Onset:IDDM -- before the age of 40

    • Peak incidence: age 14

  • Most symptoms secondary to hyperglycemia:

    • polyuria (excessive urination)

    • polydipsia (excessive thirst)

    • polyphagia (excessive or voracious eating)

  • First event may be metabolic:

    •  acute metabolic decompensation: diabetic coma

  • First event may be degenerative, e.g. neuropathy

  • Diabetic metabolic abnormalities due to:

    • relative or complete insulin deficiency

    • relative or significant glucagon access

    • metabolic decompensation may follow an increase in glucagon/insulin ratio

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• a group of milder forms of diabetes

• occurring mainly in adults

• endogenous insulin: sufficient to prevent ketoacidosis --

  • abnormal insulin secretion

  • resistance to insulin action at the tissue.

• Obesity: common risk factor

• NIDDM patients: deficiency in pancreatic B cell response to glucose

  • impaired response worsened by hyperglycemia

• Pathophysiological Phases:

  1. plasma glucose: normal -- elevated insulin levels

  2. elevated insulin levels -- postprandial hypoglycemia

  3. Insulin or systems to change -- reduced insulin secretion causes fasting hyperglycemia him (diabetes)

• Clinical Presentations:

  • NIDDM: appears in middle age or later; mainly in overweight patients

  • gradual onset of symptoms

    • Presenting symptoms:

      1.  extreme hyperglycemia

      2.  hyperosmolality

      3.  volume depletion

      4.  CNS symptoms (ranging from clouded sensorium to coma)

         1. seizure activity (Jacksonian)

         2. transient hemiplegia

      5.  Infections -- pneumonia and gram-negative sepsis (common, associated with very negative prognosis)

  • patients with NIDDM: do not develop ketoacidosis

  •  patients with NIDDM: may develop hyperosmolar, nonketotic coma

    • Syndrome properties:

      • results from sustained hyperglycemia diuresis if patient cannot drink enough water to keep up with urinary fluid loss

      • complete manifestation occurs when volume depletion decreases urine output

    • Hyperosmolar coma can occur in insulin-dependent diabetics if the insulin given is sufficient to prevent ketosis but not enough to control hyperglycemia.

  • Hyperosmolar coma can also be caused by:

    • peritoneal/hemodialysis

    • tube feeding of high-protein formulas

    • high-carbohydrate in fusion loads

    • osmotic agents (mannitol and urea)

  •   Prognosis:

    • Mortality rate and hyperosmolar coma: > 50%

  • Treatment of hyperosmolar coma states:

    • large amounts of intravenous fluids (average fluid deficit: 10-11 liters.

    • Insulin: more rapid control hyperglycemia

    • Potassium salts (counteract intracellular shifted plasma K⁺)

    • Sodium bicarbonate (if lactic acidosis present)

    • Antibiotics

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• Type II diabetes treatment: Overview

  1. diet

  2. weight reduction

  3. sulfonylurea drugs (if diet in weight reduction are inadequate)

  4. insulin may be required (in many patients)

• small protein,composed of two chains and( A & B)

• Pancreatic B cells produced proinsulin, the insulin precursor, which consists of a single-chain protein

• Proinsulin, following Golgi apparatus processing, is packaged into granules -- that hydrolyzes insulin and C-peptide

• Pancreatic B cell granules store insulin in crystals (2 atoms of zinc six molecules of insulin)

• 28 units of insulin per milligram

• Secretion:

  • normally low basal rate from pancreatic B cells

  • higher stimulated rate in response to:

    1. glucose

    2. other sugars (e.g. mannose)

    3. certain amino acids (e.g. leucine, arginine)

    4. vagal nerve activity

  • Proposed secretion mechanism:

    1. hyperglycemia

    2. increased intracellular ATP concentration

    3. higher intracellular ATP closes ATP-dependent potassium channels

    4. decreased outward potassium current causes pancreatic B cell depolarization and opens voltage-gated calcium channels

    5. increased intracellular calcium promotes insulin secretion

    6. intracellular second messengers modulate release:

       • cyclic AMP

       • inositol triphosphate

       • diacylglycerol

• Insulin Degradation:

  • circulating insulin is removed by: liver and kidney

    • Liver: clears 60% of insulin released from the pancreas

    • Kidney: clears about 35-40% of endogenous insulin (in insulin-treated diabetics -- subcutaneous injections -- the kidney may clear as much as 60%.)

  • catabolism:

    • Cleavage of sulfide linkage between A and B chains space for (catalyzed by glutathione insulin transhydrogenase and (insulinase)than

    • Further degradation: proteolysis

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•  Insulin Receptor:

  • Insulin binds to target receptors (high affinity, high specificity) and liver, muscle, and fat tissue

  • Insulin receptor: -- composition

    • two heterodimers;

      1. each containing an alpha subunit (extracellular: recognition site) and

      2. a beta subunit which spans the membrane and contains a tyrosine kinase

  • Receptor Activation:

    1.  insulin binds to alpha subunit

    2.   beta subunit increases tyrosine kinase activity, resulting in auto- phosphorylation

    3.   Phosphorylated beta subunit promotes aggregation of heterodimers and stabilizes the receptor tyrosine kinase activated state

    4.   docking protein (insulin receptor substrate-1, IRS-1) is then phosphorylated

    5.   phosphorylated IRS-1 activates other kinases, promoting further phosphorylation reactions

    6.   Insulin's second messenger's: these phosphorylation products

       • Consequence: glucose transporter translocation from sequestered sites to exposure on the cell surface

    7.   Insulin-receptor complex is then internalized

  • Alteration in Insulin receptor affinity:

    • Decrease affinity: some hormonal agents (e.g. hydrocortisone)

    • Increase affinity: (excess growth hormone)

• "Structure of the insulin receptor, a heterotetramer consisting of two extracellular insulin-binding subunits linked by a disulfide bonds to tow transmembrane beta subunits. The beta subunits contain an intrinsic tyrosine kinase activity that is activated upon insulin binding to the alpha subunit. "
• courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

• Action of Insulin: Target Sites

  • Glucose Transporters

    • GLUT 4: most important lowering blood glucose

      • found in muscle and adipose cell membranesto

      • inserted from storage vesicles

    • GLUT-2: abnormalities in GLUT-2 transport into pancreatic B cells: may contribute to reduced insulin secretion (NIDDM)

  • Liver:

    • Endogenous insulin reaches the liver first (portal circulation)

    • Hepatic Insulin Actions:

      • increases glucose storage as glycogen

      • resets liver to "fed" state -- influencing:

        1. glycogenolysis

        2. ketogenesis

        3. gluconeogenesis

      • Mechanisms for insulin-hepatic actions results, in part, from:

        • insulin-induced phosphorylations activating:

          1. pyruvate kinase

          2. phophofructokinase

          3. glucokinase

        • in the "fed" state repression of gluconeogenic enzymes occurs:

          1. pyruvate carboxylase

          2. phosphoenolpyruvate carboxykinase

          3. fructose bisphosphatase

          4. glucose 6-phosphatase

      • Insulin also decreases hepatic:

        • urea production

        • protein catabolism

        • cyclic AMP

      • Insulin promotes:

        • triglyceride synthesis

        • increases hepatic phosphate and potassium uptake

  • Muscle:

    • Insulin enhances:

      1. protein synthesis (increasing amino acid transport; stimulation of ribosyl action)

      2. glycogen synthesis

         • by increasing glucose transport to the muscle

         • inducing glycogen synthase

         • inhibiting phosphorylase

  • Adipose Tissue:

    • Insulin: reduces free fatty acids in the circulation, promoting adipocytes triglyceride storage -- three main mechanisms-- which involves cAMP production suppression and suppression of fat cell lipases:

      1. lipoprotein lipases induction

         • promotes triglyceride hydrolysis from circulating lipoproteins

      2. enhances glucose transport, promotes glycerophosphate generation: permitting fatty acids esterification

      3. reduces adipocytes intracellular lipolysis of stored triglyceride (inhibits intracellular lipase)

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• Four principal types:

  • ultra-short-acting-- (very rapid onset; short duration)

    • clear solutions; neutral pH; zinc added to enhance stability

  • short-acting --(rapid onset of action)

    • clear solutions; neutral pH; zinc added to enhance stability

  • intermediate-acting

  • long acting -- (slow onset of action)

• Insulin modifications:

  • intermediate-acting and long acting insulins:

    • turbid suspensions;neutral pH

    • protamine and phosphate buffer added (NPH insulin)

    • zinc in acetate buffer added (ultralente; lente insulins)

    • note: protamine sink insulin-- discontinued; semilente insulin preparations -- discontinued

    • Note: excess zinc in ultralente and lente insulin can precipitate some soluble regular insulin--affecting absorption

  • Subcutaneously insulin therapy: split-dose injection

    1. mixtures of short-acting and intermediate-acting insulins (NPH or lente)

    2. multiple doses of ultra-short-acting or short-acting insulin before meals in association with prolonged duration insulin (NPH, lente or ultralente suspensions) for overnight maintenance.

• Ultra-short-acting insulin:

  • Insulin lispro: new, monomeric insulin analog; recombinant technology

    • interchange of two amino acids near the B chain terminal decreases tendency to form hexameric species-- lysine-proline switch

    • insulin lispro binding to insulin receptor: unaffected by structural change

    • insulin lispro half-life: unaffected by structural change

    • insulin lispro immunogenicity: unaffected by structural change

    • Following subcutaneous administration, insulin lispro dissociates to monomers, rapidly absorbed -- peak serum values within one-hour (much more rapidly than hexameric human insulin)

    • duration of action: no more than 3-4 hours for insulin lispro.

• Short-acting insulin:

  • Regular insulin -- short-acting, soluble crystalline, zinc insulin

    • onset of action: 30 minutes

    • duration of action: 5-7 hours

    • duration and intensity of action: increases with dosage

  • Clinical Use:

    1. IV treatment for  diabetic ketoacidosis

    2. management for rapidly changing insulin requirements (e.g. post surgery, acute infection)

• Intermediate-acting and long acting insulins:

  • Lente insulin (30% semilente {rapid onset}and 70% ultralente forms {delayed onset, prolonged duration of action})

•  NPH (neutral protamine Hagedorn or isophane) insulin:

  • intermediate-acting; onset of action delayed by combining correct amounts of protamine insulin such that neither is uncomplexed.-Onset and duration of action: NPH insulin -- similar to lente insulin:

  • NPH insulin usually mixed with regular insulin: for twice daily administration

• Insulin Mixtures:

  • insulin lispro (popular, convenient pre-perennial insulin) may be mixed with a more sustained preparation for post-absorption control; acute insulin lispro mixing is acceptable:

• Insulin Species:

  • Beef and pork insulins:

    • Most commercial insulin contained: beef insulin -- primary component

    • Beef hormone: slightly more antigenic compared to pork insulin

    • common ratio: 70% beef/30% pork insulin

    • Recombinant DNA techniques have allowed mass production of human insulin

  • Human insulins:

    • Readily available: in regular, NPH, lente, or ultralente form.been

    • Premixed formulation of 70% NPH and 30% regular human insulin is available

    • Human insulin: Advantages

      1. as effective as animal insulins

      2. much less immunogenic than beef-pork insulin; slightly less immunogenic import insulin

    • Human insulin: more rapidly absorbed; slightly shorter duration of action

• Human Proinsulin:

  • available through recombinant DNA synthesis

  • Proinsulin biological activity about 8-12% that of human insulin

  • Four-six times longer circulating half-life compared to human insulin.

  • Fatal cardiovascular reactions in a group of patients receiving human proinsulin have suspended clinical trials

• Delivery systems:

  • portable pen injectors: replaced syringes

  • closed loop systems: blood glucose control a insulin infusion

  • open-loop systems (insulin pumps)

  • nasal insulin delivery: poor absorption

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• Insulin Treatment:overview

  • insulin-dependent diabetes: Type I diabetes;IDDM -- about 9% of the diabetic population

  • non-insulin dependent diabetes: Type II diabetes; NIDDM -- about 20% of Type II diabetics use insulin

• Glycemic control in diabetes mellitus

  • Tight glycemic control is advantageous except for:

    •  patients with advanced renal disease-- detrimental risks associated with hypoglycemia

    •  the elderly-- detrimental risks associated with hypoglycemia

    •  children under the age of 7 years (hypoglycemia poses a significant risk in the developing brain)

•  Complications of insulin treatment:

  • Hypoglycemia:

    • most common complication

    • causes:

      • delay in eating

      • unusual physical exertion

      • inappropriately high insulin dosage for the immediate need

    • Autonomic hyperactivity -- manifestation of hypoglycemia

      • sympathetic -- tachycardia, palpitations, sweating, tremor

      • parasympathetic-- nausea, hunger

      • Autonomic indications of hypoglycemia are less frequent perceived by elderly patients. These patients may exhibit impaired CNS function 22 hypoglycemic reactions including: mental confusion, bizarre behavior, coma

    • Treatment of hypoglycemia:

      • Glucose administration

      • For mild reactions: orange juice, glucose, sugar containing beverage, food (assumes patient is conscious)

      • For more severe hypoglycemia (unconsciousness patient):

        • intravenous infusion -- 20-50 mL. All of 50% glucose solution over a 2-3 minute interval.

        • Alternatively, in the absence of intravenous infusion, 1 mg of glucagon (subcutaneous or intramuscular administration) should restore consciousness within about 15 minutes (then allowing food consumption)

• Insulin Therapy: immunopathology

  • Insulin allergy: immediate type hypersensitivity, rare

    • urticaria follows history release from tissue mast cells (sensitized by anti-insulin IgE antibodies) the subcutaneous nodule appears that injection site {IgE-mediated complement-binding Arthus reaction}

    • antihistamines, corticosteroids, or desensitization may be required

    • less common with new, highly purified insulins

  • Immune insulin resistance:

    • due to high titer circulating IgG anti-insulin antibodies

    • Very high IgG anti-insulin antibodies require high insulin levels to compensate

    • with highly purified insulin, now available, this reaction is very rare

  • Injection site lipodystrophy:

    • atrophy of subcutaneous fat

    • rare complication due to availability of more highly concentrated insulin preparations of neutral pH

    • Hypertrophy of subcutaneous fatty tissue is a problem if insulin is injected repeatedly at the same site -- liposuction can correct

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• Oral hypoglycemics: Categories

  1. sulfonylureas, e.g. glipizide (Glucotrol)

  2. biguanides, e.g. metformin (Glucophage)

  3. competitive inhibitors of intestinal brush-border alpha-glucosidases, e.g. acarbose (Precose)

  4. thiazolidinediones-- e.g. troglitazone (Rezulin)--REMOVED FROM U.S. MARKET, rosiglitazone (Avandia)

• Sulfonylureas:

  • Mechanism of action A: promotion of insulin release for pancreatic B cells

    1. sulfonylureas bind to a pancreaticB cell potassium channel receptor

    2. potassium efflux is inhibited, causing depolarization

    3. depolarization activates a voltage-gated calcium channel, causing calcium influx

    4. insulin is released

  • Mechanism of action B: Serum glucagon concentration reduction

    1. sulfonylureas reduce serum glucagon levels -- a possible contributor to hypoglycemic effects

    2. unknown mechanism; probably indirect (secondary) inhibition due to enhanced release of both somatostatin and insulin

  • Mechanism of action C: Possible potentiation of insulin action at target tissues:

• Tolbutamide: (Orinase)

  • well absorbed; shorter duration of action

  • safest sulfonylurea for use in the elderly

  • rare acute toxic reactions

  •  some drug drug interactions (dicumarol, phenylbutazone, or some sulfonamides)

• Chlorpropamide: (Diabinese)

  • slowly metabolized; active metabolites

  • some drug drug interactions (dicumarol, phenylbutazone, or some sulfonamides)

  •  chloropropamide may induce prolonged hypoglycemia in elderly patients

  •  dilutional hyponatremia -- results from enhanced vasopressin secretion and potentiation of its effect at the renal tubule by chlorpropamide (Diabinese).

  •  rare hematologic toxicity

• Tolazamide (Tolinase)

  • comparable to chlorpropamide in potency; shorter duration of action

  • slow absorption; delayed effect on blood glucose

  • metabolized to biologically active compounds

• Acetohexamide:

  • intermediate duration of action (between Tolbutamide (Orinase) and chlorpropamide (Diabinese)-- 10-16 hours

  • hepatically metabolized to inactive metabolite

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•  Second Generation sulfonylureas: glyburide (Micronase, DiaBeta), glipizide (Glucotrol), glimepiride (Amaryl)-- fewer adverse effects

  • Glyburide: (Micronase, DiaBeta)

    • metabolized in the liver; short plasma half-life but prolonged biological effect

    • few adverse effects (not counting hypoglycemia)

    • does not cause water retention (as does chlorpropamide (Diabinese))

    •  contraindicated:

      1. hepatic impairment

      2. renal insufficiency

  • Glipizide: (Glucotrol)

    • shortest half-life (2-4 hours); extended released formulation available -- 24-hour action

    • less likely than glyburide (Micronase, DiaBeta) to produce serious hypoglycemia {due to shorter half-life}

    • extensively metabolized by the liver (90%); 10% excreted unchanged by the kidney

    •  contraindicated:

      1. hepatic dysfunction

      2. renal insufficiency

  • Glimepiride: (Amaryl)

    • monotherapy -- once a day administration or in combination with insulin

    • most potent -- lowest dose of the sulfonylureas

    • long duration of action: half-life = 5 hours

    • hepatic metabolism: complete to inactive products

• Secondary Failure and Tachyphylaxis to Sulfonylureas:

  • Treatment failures occur

  • Possibly due to pancreatic B cell refractoriness or to loss of dietary compliance

• Combination of sulfonylureas and insulin would appear justified only in the presence of severe insulin resistance

• Metformin: (Glucophage)

• Proposed Mechanism of Action:

  1. glycolysis stimulation-- increased glucose removal from blood

  2. decreased hepatic gluconeogenesis

  3. decreased glucose absorption rate from the GI tract

  4. reduced plasma glucagon

• Clinical Use:

  • in patients with refractory obesity and insulin resistance

    • Advantages:

      • does not cause hypoglycemia

      • does not increased weight

  • May be used in combination with sulfonylureas when sulfonylurea monotherapy is not effective

•   Toxic/adverse effects:

  • most common -- gastrointestinal (20% frequency)

    • anorexia, nausea, vomiting, diarrhea

    • dose-related

    • usually occurs upon initiation of therapy -- often transient in effect

  •  Decreased vitamin B₁₂ absorption; may require vitamin B₁₂ supplementation

  •  Contraindicated in:

    • renal disease

    • alcoholism

    • hepatic disease

    • chronic cardiopulmonary disease (its associated with tissue hypoxia --biguanides may increase the risk of lactic acidosis)

• Acarbose (Precose)

  • oligosaccharide analog -- strongly binds to intestinal disaccharidases (e.g. alpha-glucosidase)

    • Competitive in addition of alpha-glucosidase reduces postprandial glucose rise (reduction: 30-50%)

  • results in delayed carbohydrate absorption:

    • starches, dextrins, maltose, sucrose (not lactose)

  •  Adverse Effects:

    • most common: flatulence

    • hypoglycemia may occur or give used in combination with insulin or sulfonylureas

  •  Drug-drug interaction: acarbose interferes with metformin absorption

• Miglitol (Glyset)

  • similar to acarbose (Precose) but possibly with less hepatotoxicity

  • Acarbose (Precose) and miglitol (Glyset) have similar similar gastrointestinal effects

• Troglitazone (Rezulin)-- FDA approved for insulin resistant patients who are receiving insulin

  •  REMOVED FROM U.S. MARKET--MARCH 2000

  • Mechanism of Action:

    • Increases tissue insulin sensitivity

  • Clinical Effectiveness:

    • decreased insulin resistance

    • decreased insulinemia

    • reduced fasting and postprandial hyperglycemia in Type II diabetics (non-insulin dependent diabetics, NIDDM)

• Rosiglitazone* (Avandia)-- FDA approved for management of Type II diabetes

  • Approval as monotherapy or in combination with metformin (Glucophage)

    • might be used with insulin or a sulfonylurea

    • Apparently as effective does troglitazone (Rezulin) in controlling blood glucose without liver toxicity

    • Long-term safety/benefits of rosiglitazone (Avandia) in patients with Type II diabetes: yet to be determined.

  • Pharmacokinetics:

    • Well absorbed following oral administration (half-life: 3-4 hours)

    •  Hepatic metabolism

  •  Adverse Effects:

    •  absence of liver failure; no drug-related jaundice!

    •  no ALT (alanine aminotransferase) abnormalities reported in clinical trials

    • fluid retention-- similar to that seen with troglitazone (Rezulin)

    • increases in LDL & HDL cholesterol-- about 15%

  • Precautions:

    • Thiozolidinediones may cause hepatotoxicity--Package insert recommends:

      • ALT determination prior to treatment and every two months for one-year, then periodically

      • ALT levels > 2.5 times above upper normal limit: do not start treatment

      • After treatment initiation, ALT levels > 3 times above normal: stop treatment

• Pioglitazone (Actos)

  • Overview

    • Pioglitazone (Actos): thiozolidinedione, reduce insulin resistance

  • Clinical use:

    • May be used as monotherapy

    • May be used in combination with a sulfonylurea,metformin (Glucophage), or insulin

  •  Adverse Effects:

    • Moderate weight gain

    • edema, mild anemia

    • No reports of hepatic toxicity (Liver function monitoring every two months -- recommended)

  • Conclusion: pioglitazone (Actos) similar to rosiglitazone (Avandia) effectiveness; long-term safety unknown

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• Overview

  • Glucagon, a peptide, produced by A cells of the pancreatic islets of Langerhans

  • Glucagon is arrived from a large precursor peptide (one intermediate: glicentin, 69-amino acid peptide)

  • Rapidly inactivated in plasma (degraded also at hepatic, renal, and tissue receptor sites)

• Enteroglucagons:

  • Glicentin immunoreactivity: cells of the small intestine, pancreatic A cells, pancreatic effluent-- glucagon-like peptides

• Glucagon: Pharmacological activity

  • Metabolic:

    1. glucagon interacts with specific, hepatic receptors

    2. G protein activation, increase in adenylyl cyclase activity, increases cAMP production

    3. Increased catabolism of stored glycogen, increased gluconeogenesis, increased ketogenesis

  • Pharmacological consequences:

    • increased blood glucose, decreased hepatic glycogen

    • insulin released from normal pancreatic B cells

    • catecholamines from pheochromocytoma

    • calcitonin from medullary carcinoma

  • Cardiovascular Effects:

    • positive inotropic action (increased myocardial contractility)

    • positive chronotropic (increased heart rate)

    • these effects mediated by cAMP

  • Smooth Muscle Effects:

    • (large doses): intestinal smooth muscle relaxation

• Clinical Use:

  • Management of Severe Hypoglycemic States

    • emergency treatment in insulin-dependent unconscious patients in which intravenous glucose cannot be administered (a conscious patient would be treated by drinking orange juice or other high sugar content foods)

    • Glucagon is available for parenteral use.

  • Endocrine Diagnoses/Analysis:

    • evaluation of pancreatic B cell secretory insulin reserve

    • provocative hormonal discharge from suspected:

      • insulinoma

      • pheochromocytoma

      • thyroid medullary carcinoma

  • Beta-blocker Overdosage: (useful for enhancing myocardial performance independent of the beta-receptor)

  • Diagnostic Radiology: glucagon-induced intestinal relaxation assists in radiological assessment of the bowel.

•  Adverse Effects

  • transient nausea/vomiting -- generally mild

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