The Endocrine Pancreas      1 million islets of Langerhans  

Cell Types ApproximatePercent of Islet Mass

Secretory Products

A cells (Alpha) 20 GlucagonProglucagon

B cells (Beta) 75 Insulin, C-peptide,

proinsulin, islet amyloid

polypeptide (IAPP) or amylin

D cells (Delta)

3-5 Somatostatin

F cells (PP cells)

<2 Pancreatic polypeptide

    

Different Forms of Diabetes Mellitus General – genetic and other factors not precisely defined Type 1 (Insulin-Dependent Diabetes Mellitus)

Autoimmune type 1 DM type 1A) Non-autoimmune or idiopathic type 1 DM (type 1B)

Type 2 (Non-insulin Dependent Diabetes Mellitus)Specific – defined gene mutations Maturity-onset diabetes of youth (MODY)MODY 1 hepatic nuclear factor 4α (HNF4A) gene mutationsMODY 2 glucokinase (GCK) gene mutationsMODY 3 hepatic nuclear factor 1α (TCF1) gene mutationsMODY 4 insulin promoter factor 1 (IPF1) gene mutationsMODY 5 hepatic nuclear factor 1β (HNF1β) gene mutationsMODY 6 neurogenic differentiation 1 (NEUROD1) gene mutationMODY X unidentified gene mutation(s) Maternally inherited diabetes and deafness (MIDD) Mitochomdrial leucine tRNA gene mutations Insulin gene mutations Insulin receptor gene mutationsDiabetes secondary to pancreatic disease Chronic pnacreatitis Surgery Tropical diabetes (chronic pancreatitis asst’d with nutritional and/or toxic factors)Diabetes secondary to other endocrinopathies Cushing’s disease Glucocorticoids administration Acromegaly Diabetes secondary to immune suppressionDiabetes associated with genetic syndrome (Prader-Willi syndrome)Diabetes associated with drug therapy    

Some Drugs That Cause Hypoglycemia or Hyperglycemia

Drugs with Hypoglycemic Effects: Drugs with Hyperglycemic Effects:Beta-adrenergic receptor antagonists EpinephrineSalicylates GlucocorticoidsIndomethacin DiureticsNaproxen Atypical antipsychoticEthanol HIV-1 protease inhibitorsClofibrate DiazoxideACE inhibitors Beta2 adrenergic agonistsLi+ Ca++ channel blockersTheophyllin PhenytoinCa++ ClonidineBromocriptine H2-receptor blockersMebendazole PentamidineSulfonamides MorphineSulbactam-ampicillin HeparinTetracycline Nalidixic acidPyridoxine SulfinpyrazonePentamidine Marijuana

Nicotine

Insulin:     

Chemistry:   * a small protein with molecular weight of 5808   * contains 51 amino acids   * arranged in 2 chains ( A & B ) linked by disulfide

bonds/bridges   * stored crystals consisting of 2 atoms of zinc & 6

molecules of insulin    * contain 8mg of insulin/human pancreas (=200 units) 

Insulin secretion:-          - respond to a variety of stimuli ( glucose, mannose, leucine, arginine & vagal activity)   

Insulin Degradation:-         2 main organs: liver – 60% kidney – 35-40%-         hydrolysis of the disulfide bonds glutathione insulin

transhydrogenase (insulinase )-       half-life: 3-5 minutes  Measurement of Circulating Insulin:-         radioimmunoassay permits detecton of insulin in picomolar quantities-         basal insulin values: 5-15uU/ml (30-90pmol/L)-         peak rise: 60-90uU/ml (360-540pmol/L) 

The Insulin Receptor: 

Effects of Insulin on its Targets A. Action of Insulin on Glucose Transporters:

Transporters Tissues GlucoseKm (Mmo/L)

Function

GLUT 1 All tissues, esp.red cells, brain

1-2 Basal uptake of glucose;Transport across the BBB

GLUT 2 B cells of pancreas;Liver; kidney; gut

15-20 Regulation of insulin release, other aspects of glucose homeostasis

GLUT 3 Brain, kidney, placenta, other tissues

< 1 Uptake into neurons, other tissues

GLUT 4 Muscle, adipose 5 Insulin-mediated uptake of glucose

GLUT 5 Gut, kidney 1-2 Absorption of fructose

 B.             Action of Insulin on Liver-         inhibits hepatic glucose production (decreases gluconeogenesis & glycogenolysis)-         stimulates hepatic glucose uptake  

C.             Effect of Insulin on Muscle-         stimulates glucose uptake-         inhibits flow of gluconeogenic precursors to the liver (alanine, lactate & pyruvate) 

D.            Effect of insulin on Adipose Tissue-         stimulate glucose uptake (amount is small compared to muscle)- inhibits flow of gluconeogenic precursor to liver (glycerol) and reduces energy substrate for hepatic gluconeogenesis (non-esterified fatty acids)

 

A. Principal Types and Duration of Action 1. Short- and Rapid-acting insulins: = Regular insulin ( soluble crystalline zinc ) = Insulin lispro, Insulin aspart, insulin glulysine = Permit more physiologic prandial insulin replacement = Taken immediately before meal without sacrificing glucose control= With very fast onset (5-15 min, 10-20 min. & 30 minutes after SQ) and short duration (3-5 hours & 5-8 hours)   = Peak serum values: 1 hour & 2 & 3 hours = The only type that should be administered intravenously = Useful in the management of diabetic ketoacidosis, surgery or during acute infection, and when the insulin requirement is changing rapidly

               1. Intermediate-acting a.    LENTE INSULIN (insulin zinc suspension)mixture of 30% semilente with 70% ultralente insulin provide a combination of relatively rapid absorption with sustained long action b.NEUTRAL PROTAMINE HAGEDORN or Isophane Insulinabsorption & onset of action is delayed by combining appropriate amounts of insulin & protamine6 molecules of insulin per molecule of protamine 3. Long-acting insulinsa.  ULTRALENTE INSULIN (extended insulin zinc suspension) b.  PROTAMINE ZINC INSULIN SUSPENSIONthey have slower onset and a prolonged peak of actionrecommended dose be split into 2 or more doses c. INSULIN GLARGINEsoluble, “peakless, ultra-long-acting insulin analog

designed to provide reproducible, convenient, background insulin replacement

  has a slow onset of action (1-1.5 hours)

achieves a maximum effect after 4-5 hours and maintained for 11-24 hours or longergiven once a day

 A Species of Insulin1.      Beef and pork insulins    The beef insulin differs by 3 amino acids, pork differs by 1 amino acid    The beef hormone is most antigenic 2. Human insulins    Less expensive, less immunogenic  Production by recombinant DNA techniques B.     Purity of Insulin    Chromatography C.     Concentration 100 units/ml, 500 units/ml

 

Insulin Delivery Systems A.  Portable Pen Injectors    to facilitate multiple SQ injections  B. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps)    encouraged for individuals who are unable to obtain target control while on multiple injection regimens & where excellent glycemic control is desired, such as during pregnancy    velosulin (reg. insulin) & insulin aspart and lispro C.   Inhaled Insulin    have a rapid route and a relatively short duration of action    used to cover mealtime insulin requirements     to correct high glucose levels 

Factors that Affect Insulin Absorption:-      site of injection: abdomen, buttock, anterior thigh, or dorsal arm-         type of insulin-         subcutaneous blood flow: massage, hot baths, or exercise-         smoking-         regional muscular activity at the site of the injection-         volume & concentration of injected insulin-         depth of injection  Treatment With Insulin     Type 1 patients    Type 2    Contraindication: advanced renal disease Elderly

Complications of Insulin Therapy A.  Hypoglycemia1.      Mechanisms and diagnosis    result from a delay in taking a meal    unusual physical exertion    dosage error    CM: tachycardia, palpitations, sweating, tremulousness, hunger, nausea, convulsion, coma    Treatment: glucose administration Glucagons 1 mg SQ or IM Honey or syrup B.   Immunopathology of Insulin Therapy 1. Insulin allergy    an immediate type of hypersensitivity (IgE-antibodies)    Tx: antihistamines, corticosteroids & desensitization 2.    Immune insulin resistance (IgG antibodies)    + circulating antibodies that neutralize the action of insulin to a small extent    Tx: switching to a lesser antigenic purified insulin C.   Lipodystrophy at injection sitescorrected by avoidance of that specific injection site or with liposuction – hypertrophy

Oral Anti-diabetic Agents 4 Categories: a. Insulin secretagogues (sulfonylureas, meglitinides,

D-phenylalanine derivatives)b.    Biguanidesc.    Thiazolidinedionesd.    Alpha-glucosidase inhibitors 

Insulin Secretagogues:A. Sulfonylureas  Mechanism of Action:    to increase insulin release from pancreatic B cells Sulfonylureas bind to S receptorinhibits efflux of K+depolarizationopens a voltage-gated Ca++ channelresults in Ca++ influx and the release of preformed insulin reduction of serum glucagon concentrations Chronic adm’n of sulfonylureas to type 2 diabetics reduces serum glucagon levels  potentiation of insulin action on target tissues

First Generation Sulfonylureas Tolbutamide:     well absorbed but rapidly metabolized in the liver    duration of action: 6-12 hours    elimination half-life: 4-5 hours    toxic reactions: skin rash hypoglycemia    drug interactions: dicumarol, phenylbutazone, sulfonamides Chlorpropamide:    duration of action: up to 60 hours    half-life: 32 hours    slowly metabolized in the liver    20-30% is excreted unchanged in the urine    SE: hypoglycemia, hyperemic flush, dilutional hyponatremia, transient leukopenia, thrombocytopenia, jaundice    CI: hepatic & renal insufficiency    Dosage: 250mg daily Tolazamide:    duration of action: 10-14 hours    more slowly absorbed    half-life: 7 hours    SE: hypoglycemia      

Second Generation SulfonylureasGlyburide:    metabolized in the liver    short plasma half-life    duration of action: 10-24 hours    SE: flushing, hypoglycemia    Contraindication: hepatic & renal insufficiency    Dosage: 5-10mg as single morning dose Glipizide:    has the shortest half-life: 2-4 hours    duration of action: 10-24 hours    90% is metabolized in the liver    10% excreted unchanged in the urine    SE: hypoglycemia    Contraindication: renal & hepatic insufficiency    Dosage: 5-20mg as a single dose, 30 minutes before breakfast Glimepiride:    duration of action: 12-24 hours    half-life: 5 hours    available as once-daily dosing    completely metabolized by the liver    dosage: 1 mg daily   

 B. MeglitinidesRepaglinide:    modulate B cell insulin release by regulating K+ efflux through the K+ channels    no direct effect on insulin exocytosis    peak conc & peak effect: within 1 hour    fast onset & duration of action (5-8 hrs.)    hepatically cleared by CYP3A4    half-life: 1 hour    indication: controlling postprandial glucose excursions    Dosage: 0.25-4 mg    SE; hypoglycemia    Caution: hepatic & renal impairment C. D-phenylalanine derivativeNateglinide:  stimulates very rapid and transient release of insulin from B cells through the closure of ATP-sensitive K+ channel    may suppress glucagons release early in the meal and result in less endogenous or hepatic glucose production    has minimal effect on overnight or fasting blood glucose levels    ingested just prior to meals    absorbed within 20 minutes after oral administration    time to peak concentration: < 1 hour    hepatically metabolized by CYP2C9 & CYP3A4    half-life: 1.5 hours    duration of action: < 4 hours    SE: hypoglycemia but lowest of all the secretagogues 

 BiguanidesMechanism of action:-         direct stimulation of glycolysis in tissues, with increased glucose removal from blood-         reduced hepatic & renal gluconeogenesis-         slowing of glucose absorption from the GIT, with increased glucose to lactate conversion by enterocytes-         reduction of plasma glucagon levelsMetabolism & Excretion:Metformin:    half-life: 1.5-3 hours    duration of action: 10-12 hours    not bound to plasma proteins    not metabolized     excreted by the kidneys as active compound    may impair the hepatic metabolism of lactic acidClinical Uses:-  refractory obesity whose BS is due to ineffective insulin action (insulin resistance

syndrome)-         use as in combination with sulfonylureas or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate-         dosage: 500mg TIDToxic Effects:    anorexia, nausea, vomiting, abdominal discomfort, diarrhea    absorption of B12 appears to be reduced during long-term therapy Containdications:    renal disease, alcoholism    hepatic disease    chronic cardiopulmonary dysfunction

 Thiazolidinediones    Act to reduce insulin resistance     Primary action: nuclear regulation of gene involved in glucose and lipid

metabolism and adipocyte differentiation    Are ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma)    Have significant effects on vascular endothelium, the immune system, the

ovaries and tumor cells    In diabetes, a major site of action is adipose tissue, where the drug promotes

glucose uptake and utilization and modulate synthesis of lipid hormones or cytokines and other proteins involved in energy regulation

    Also regulate adipocyte apoptosis & differentiation     Are considered “euglycemics”    Have a slow onset and offset of activity     SE: hypoglycemia in combination

Drop in triglyceride levelsSlight rise in HDL & LDL cholesterol valuesEdema – fluid retentionAnemiaDose-related weight gain (1-3 kg)

     CI: pregnancy Significant liver disease Heart failure

Pioglitazone:    may have PPAR-alpha as well as PPAR-gamma activity    absorbed within 2 hours of ingestion    metabolized by CYP2C8 and CYP3A4 to active metabolites    DI: estrogen-containing oral contraceptives    Taken once daily    Dosage: 15-30mg   Approved as monotherapy or in combination with metformin, sulfonylureas, and insulin Rosiglitazone:    rapidly absorbed and highly protein bound    metabolized in the liver by CYP2C8 & CYP2C9    administered once or twice daily    dosage: 4-8 mg   approved as monotherapy or in combination with biguanides & sulfonylureas 

Alpha-Glucosidase Inhibitors-  are competitive inhibitors of the intestinal alpha-glucosidases and reduce the postprandial digestion and absorption of starch and disaccharides--> lowering postmeal glycemic excursions (45-60mg/dl) and creating an insulin-sparing effect

-   members: acarbose & miglitol

-  taken in doses of 25-100 mg just prior to ingesting the first portion of each meal

-   both are absorbed from the gut

-   SE: flatulence, Diarrhea, Abdominal pain

- CI: Chronic or inflammatory bowel disease, Renal impairment, Hepatic disease (acarbose)