1 sulfonylureas reduce fasting and ppg should be initiated at low doses increased at 1- to 2-week...

1

Sulfonylureas Reduce fasting and PPG should be initiated at low doses Increased at 1- to 2-week intervals based on

SMBG. Increase insulin acutely and thus should be

taken shortly before a meal With chronic therapy, the insulin release is

more sustained

2

Repaglinide

Is not a sulfonylurea but also interacts with the ATP-sensitive potassium channel.

short half-life

usually given with or immediately before each meal to reduce meal-related glucose excursions.

3

Insulin secretagogues

Are well tolerated in general.

All of these agents, have the potential to cause profound and persistent hypoglycemia, especially in elderly individuals.

5

Sulfonylureas

Most sulfonylureas are metabolized in the liver to compounds that are cleared by the kidney.

Their use in individuals with significant hepatic or renal dysfunction is not advisable.

Weight gain, a common side effect of SUD, results from the increased insulin and improvement in glycemic control

6

Sulfonylureas Some sulfonylureas have significant drug

interactions with other medications such as Alcohol Warfarin Aspirin ketoconazole a-glucosidase inhibitors Fluconazol

7

Biguanides: Mechanisms of Action

1. Intestine: glucose absorption 2. Muscle and adipose tissue:Biguanides glucose utilization

3. Pancreas: insulin secretion

4. Liver: Biguanides hepatic glucose output

Insulin resistance

Insulin resistanceBlood glucose

DeFronzo et al. J Clin Endocrinol Metab 1991;73:1294-1301.Stumvoll et al. N Engl J Med 1995;333:550-554.

Treating to Target

8

BIGUANIDES

Metformin Reduces hepatic glucose production through

an undefined mechanism May improve peripheral glucose utilization

slightly. Reduces fasting plasma glucose and insulin

levels Improves the lipid profile Promotes modest weight loss.

9

Metformin

The initial starting dose of 500 mg once or twice a day can be increased to 850 mg tid or 1000 mg bid.

Because of its relatively slow onset of action and gastrointestinal symptoms with higher doses, the dose should be escalated every 2 to 3 weeks

12

Metformin The major toxicity lactic acidosis Metformin should not be used in patients with

RF [creatinine >1.5 in men or >1.4 mg/dL in women]

Any form of acidosis CHF Liver disease Severe hypoxia.

13

Metformin

Metformin should be discontinued in patients

Who are seriously ill

Patients who can take nothing orally

Those receiving radiographic contrast

14

METFOMIN

Some develop GI side effects (diarrhea, anorexia, nausea, and metallic taste) that can be minimized by gradual dose escalation.

Drug is metabolized in the liver

It should not be used in patients with liver disease or heavy ethanol intake

15

Alpha-Glucosidase Inhibitors:Mechanisms of Action

1. Intestine: glucose absorption

2. Muscle and adipose tissue: glucose uptake

3. Pancreas: insulin secretion

4. Liver: hepatic glucose output

Insulin resistanceBlood glucose

Insulin resistance

Amatruda. From Diabetes Mellitus, Ch. 72,1996,p. 643-648.

Treating to Target

16

a-GLUCOSIDASE INHIBITORS

a-Glucosidase inhibitors (acarbose and miglitol) reduce pp hyperglycemia by delaying glucose absorption

They do not affect glucose utilization or insulin secretion.

PP hyperglycemia, contributes significantly to the hyperglycemic state in type 2 DM.

17


These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen.

18


Therapy should be initiated at a low dose (25 mg of acarbose or miglitol)

with the evening meal and may be increased to a maximal dose over weeks to months (50 to 100 mg for acarbose or 50 mg for miglitol with each meal).

19


The major side effects (diarrhea, flatulence, abdominal distention) are related to increased delivery of oligosaccharides to large bowel

a-Glucosidase inhibitors may increase SUD and increase hypoglycemia.

Simultaneous treatment with bile acid resins and antacids should be avoided.

20


These agents should not be used in IBD Gastroparesis Creatinine >2.0 mg/dL.

This agents is not as potent as other oral agents in lowering the HbA1c but is unique in that it reduces the PP glucose rise even in individuals with type 1 .

21

THIAZOLIDINEDIONES

Thiazolidinediones represent a new class of agents that reduce insulin resistance.

These drugs bind to a nuclear receptor (peroxisome proliferator-activated receptor, PPAR-g) that regulates gene transcription.

23

Glitazones Mechanism of Action

peroxisome-proliferator-activated receptor-peroxisome-proliferator-activated receptor-gamma PPARgamma PPAR - most important receptor - most important receptor isoformisoformreduces TNF-reduces TNF- and hepatic glucokinase and hepatic glucokinase

expression (expression (suppresses glucose outputsuppresses glucose output)) Stimulate expression of genes responsible for Stimulate expression of genes responsible for

production of GLUT-1 and GLUT-4 (production of GLUT-1 and GLUT-4 (increases increases insulin sensitivity 60%insulin sensitivity 60%))

24

Thiazolidinediones:Mechanisms of Action

Muscle andadipose tissue insulin resistance glucose uptake

Liver insulin resistance hepatic glucose

production

Bloodglucose

Pancreas demand for insulin secretion beta-cell insulin content

Balfour, et al. Drugs 1999;57:921-930.Whitcomb, et al. From Diabetes Mellitus, Ch. 74, p. 661-668.

Treating to Target

25

Translation into proteinsTranslation into proteins GLUT, GLUT, LPLLPL

Thiazolidinedione - Mechanisms of Action

PPAR PPAR RXRRXR

Metabolic Effects

Glucose uptake, Tg clearance

Metabolic EffectsMetabolic Effects

Glucose uptake, Glucose uptake, TgTg clearance clearance

Transcription of GenesTranscription of Genes

mRNA mRNA GLUT, GLUT, mRNAmRNA LPL LPL

Adapted from: Tan M. (2000) Exp Clin Endocrinol Diabetes Suppl 2 108;S 224

TZDTZD

26

Rosiglitazone

N N

CH3

OS

NH

O

O

Pioglitazone

N

CH3 CH2

OS

NH

O

O

Thiazolidinediones: Structures

Treating to Target

27

THIAZOLIDINEDIONES

Agonists of this receptor promote adipocyte differentiation may reduce insulin resistance in skeletal muscle

indirectly. TZD reduce the fasting glucose by improving

peripheral glucose utilization and insulin sensitivity

28

THIAZOLIDINEDIONES

Circulating insulin decrease with use of the TZDs, indicating a reduction in insulin resistance.

Therapeutic range for pioglitazone is 15 to 45 mg/d in a single daily dose and for rosiglitazone is 2 to 8 mg/d

29

THIAZOLIDINEDIONES

TZD raise LDL and HDL slightly and lower TG by 10 to 15%

TZD are associated with weight gain (1 to 2 kg) small reduction of HCT a mild increase in plasma volume. Cardiac function is not affected, but the

incidence of peripheral edema is increased

30

THIAZOLIDINEDIONES

They are contraindicated in patients with liver disease or CHF (class III or IV).

TZD have been shown to induce ovulation in premenopausal women with polycystic ovary syndrome

31

INSULIN THERAPY IN TYPE 2 DM

Insulin should be considered as the initial therapy in type 2 DM, particularly in

Lean individuals Severe weight loss Underlying renal or hepatic disease Individuals who are hospitalized Acutely ill

32


Insulin is usually initiated in a single dose of intermediate-acting (0.3 to 0.4 U/kg/day), given either before breakfast or just before bedtime (or ultralente at bedtime).

34


Since fasting hyperglycemia and increased

hepatic glucose production are prominent features of type 2

bedtime insulin is more effective than a single dose of morning insulin.

35


Both morning and bedtime intermediate insulin may be used in combination with oral glucose-lowering agents (biguanides, a-glucosidase inhibitors, or thiazolidinediones).

36

CHOICE OF INITIAL GLUCOSE-LOWERING AGENT

most patients and physicians currently prefer oral glucose-lowering drugs as the initial pharmacologic approach.

The level of hyperglycemia should influence

the initial choice of therapy

37


Mild to moderate hyperglycemia [fasting plasma glucose < (200 to 250 mg/dL)] often respond well to a single oral glucose-lowering agent.

More severe hyperglycemia [fasting plasma glucose > 250 mg/dL] may respond partially but are unlikely to achieve normoglycemia with oral monotherapy.

38


Some physicians begin insulin in individuals with severe hyperglycemia [fasting glucose > 250 to 300 mg/dL].

39


Insulin secretagogues biguanidesa-glucosidase inhibitors thiazolidinediones insulin are approved for monotherapy

of type 2 .

40


insulin secretagogues, biguanides, and TZD improve glycemic control to a similar degree (1 to 2% reduction in HbA1c) and are more effective than a-glucosidase inhibitors

41


insulin secretagogues and a-glucosidase inhibitors begin to lower the plasma glucose immediately

glucose-lowering effects of the biguanides and TZD are delayed by several weeks to months

42


Biguanides a-glucosidase inhibitors TZD

do not directly cause hypoglycemia

43

COMBINATION THERAPY WITH GLUCOSE-LOWERING AGENTS

Commonly used regimens include: (1) insulin secretagogue with metformin or

TZD (2) SUD with a-glucosidase inhibitor

(3) insulin with metformin or TZD. The combination of metformin and a TZD is

also effective and complementary

46

Characteristics of an Ideal Basal Insulin

Closely mimic normal pancreatic basal insulin Closely mimic normal pancreatic basal insulin secretionsecretion

No distinct peak effectNo distinct peak effect Continued effect over 24 hoursContinued effect over 24 hours Reduce nocturnal hypoglycemiaReduce nocturnal hypoglycemia Once-daily administration for patient convenienceOnce-daily administration for patient convenience Predictable absorption patternPredictable absorption pattern

47

EffectiveEffectiveOnsetOnset PeakPeak DurationDuration

Insulin lisproInsulin lispro <15 min<15 min 0.5-1.5 hr0.5-1.5 hr 3-4 hr3-4 hrRegularRegular 0.5-1 hr0.5-1 hr 2-3 hr2-3 hr 3-6 hr3-6 hrNPHNPH 2-4 hr2-4 hr 6-10 hr6-10 hr 10-16 hr10-16 hrLente 3-4 hr 6-12 hr 12-18 hrLente 3-4 hr 6-12 hr 12-18 hrUltralenteUltralente 6-10 hr6-10 hr 10-16 hr10-16 hr 18-20 hr18-20 hrGlargine 4 - 24Glargine 4 - 24

Pharmacokinetics of Current Insulin Preparations

48

The Basal/Bolus Insulin ConceptBasal InsulinBasal Insulin

Suppresses glucose production between meals and overnightSuppresses glucose production between meals and overnight Nearly constant levels Nearly constant levels 50% of daily needs50% of daily needs

Bolus Insulin (Mealtime or Prandial)Bolus Insulin (Mealtime or Prandial) Limits hyperglycemia after mealsLimits hyperglycemia after meals Immediate rise and sharp peak at 1 hour Immediate rise and sharp peak at 1 hour 10% to 20% of total daily insulin requirement at each meal10% to 20% of total daily insulin requirement at each meal

Ideally, for insulin replacement therapy, each component Ideally, for insulin replacement therapy, each component should come from a different insulin with a specific profileshould come from a different insulin with a specific profile

6-20

49

Problems with Human Insulin Profiles Short-acting insulin (regular insulin)Short-acting insulin (regular insulin)

Absorbed too slowly to match glucose peakAbsorbed too slowly to match glucose peak Intermediate/Long-acting insulins (NPH, Lente, Intermediate/Long-acting insulins (NPH, Lente,

UL)UL) Absorbed too quickly to mimic basal Absorbed too quickly to mimic basal

secretionsecretion These insulins have a peak effectThese insulins have a peak effect Short duration of action- need for multiple Short duration of action- need for multiple

injectionsinjections

50

Meal Time (Bolus) Insulin

Regular insulinRegular insulin Dosed 30-45 minutes prior to mealDosed 30-45 minutes prior to meal Longer duration of action (up to 4-6 hours)Longer duration of action (up to 4-6 hours) Can result in between-meal hypoglycemiaCan result in between-meal hypoglycemia

New Rapid acting insulin analogues (Aspart, Lispro)New Rapid acting insulin analogues (Aspart, Lispro) Dose given immediately pre-mealDose given immediately pre-meal Onset - 15 minutes, peak effect 30-90 minutesOnset - 15 minutes, peak effect 30-90 minutes Improved post-meal glucose controlImproved post-meal glucose control Limits risk of hypoglycemiaLimits risk of hypoglycemia

51

Activity Profile of Insulin Lispro

0 60 120 180 240 300 360 420 480

Meal Minutes

Normal insulin response

Regular human insulin (injection 5 minutes before meals)

Insulin Lispro (injection 5 minutes before meals)*

* Aspart has similar profile

Adapted from Pampanelli S et al. Diabetes Care 1995;18:1452-1459

Based on a study of 6 patients with type 1 diabetes and some residual -cell function and 6 control subjects without diabetes

Insulin (mU/L)

60

50

40

30

20

10

0

52

Insulin Aspart/Lispro

Ultra-short-acting insulin analoguesUltra-short-acting insulin analogues Controls postprandial glucose excursions Controls postprandial glucose excursions Compared with regular human insulin:Compared with regular human insulin:

Reduces incidence of hypoglycemiaReduces incidence of hypoglycemia Questionable improvement in HbAQuestionable improvement in HbA1c1c

Thorsby P et al. European Association for the Study of Diabetes 1999. Abstract 57Home PD, et al. European Association for the Study of Diabetes 1999. Abstract 60

53

Available Basal Insulins NPH, LenteNPH, Lente

Generally dosed twice daily (AM, PM or Generally dosed twice daily (AM, PM or HS)HS)

Peak effect 4-8 hours after injectionPeak effect 4-8 hours after injection UltralenteUltralente

has a peak effecthas a peak effect variable pharmacokineticsvariable pharmacokinetics human UL does not last 24 hourshuman UL does not last 24 hours

Glargine (Lantus)Glargine (Lantus) Once daily, no peak actionOnce daily, no peak action

54

Pharmacokinetics of Insulin Glargine (Lantus®)

Compared with NPH insulin:Compared with NPH insulin: Slower, more prolonged absorptionSlower, more prolonged absorption Lack of peak serum concentrationLack of peak serum concentration

Allows for once-daily administrationAllows for once-daily administration Intrapatient variability comparable with NPH Intrapatient variability comparable with NPH

insulininsulin Less intrapatient variability than ultralente insulinLess intrapatient variability than ultralente insulin Cannot be mixed in the same syringe with other Cannot be mixed in the same syringe with other

insulinsinsulins

58

Meal Time (Bolus) Insulin

Regular insulinRegular insulin Dosed 30-45 minutes prior to mealDosed 30-45 minutes prior to meal Longer duration of action (up to 4-6 hours)Longer duration of action (up to 4-6 hours) Can result in between-meal hypoglycemiaCan result in between-meal hypoglycemia

New Rapid acting insulin analogues (Aspart, Lispro)New Rapid acting insulin analogues (Aspart, Lispro) Dose given immediately pre-mealDose given immediately pre-meal Onset - 15 minutes, peak effect 30-90 minutesOnset - 15 minutes, peak effect 30-90 minutes Improved post-meal glucose controlImproved post-meal glucose control Limits risk of hypoglycemiaLimits risk of hypoglycemia

59

Indications for Insulin Therapy in Type 2 Diabetes

Presence ketonuria in unstressed statePresence ketonuria in unstressed state Nonobese with persistently elevated glucose leveles (FBS Nonobese with persistently elevated glucose leveles (FBS

greater than 250-300 )greater than 250-300 ) Symtpoms of polyuria, polydipsia and weight loss and Symtpoms of polyuria, polydipsia and weight loss and

hyperglycemiahyperglycemia Severe hypertriglyceridemiaSevere hypertriglyceridemia Oral agent failure with or without symptomatic Oral agent failure with or without symptomatic

hyperglycemiahyperglycemia GDMGDM whose disease is not controlled with diet alone and whose disease is not controlled with diet alone and

women with type 2 diabetes who become pregnantwomen with type 2 diabetes who become pregnant

60

Rationale for Insulin Therapy in Type 2 Diabetes (1) Peripheral resistance to insulin actionPeripheral resistance to insulin action and and

impaired pancreatic B-cell secretionimpaired pancreatic B-cell secretion are are early and primary abnormalitiesearly and primary abnormalities

Increased hepatic glucose production Increased hepatic glucose production is ais a late and secondary manifestationlate and secondary manifestation

61

Rationale for Insulin Therapy in Type 2 Diabetes (2)

Progressive hyperglycemia Progressive hyperglycemia decrease in B- decrease in B-cell function in UKPDScell function in UKPDS

deteriorated significantly in deteriorated significantly in diet-treated groupdiet-treated group, , from from 53% at yr 1 to 26% at yr 653% at yr 1 to 26% at yr 6

62

Rationale for Insulin Therapy in Type 2 Diabetes (2) in in sulfonylurea groupsulfonylurea group, an early increase in B-, an early increase in B-

cell function from cell function from 45% to 78% in yr 145% to 78% in yr 1, but , but subsequently decreased to subsequently decreased to 52%52%

in in metformin groupmetformin group, B-cell function declined , B-cell function declined from from 66% to 38% at yr 666% to 38% at yr 6

Over the course of 15 yrs, the proportion of Over the course of 15 yrs, the proportion of patients using oral agents declines, and most patients using oral agents declines, and most will will require exogenous insulin treatmentrequire exogenous insulin treatment

63

Benefits of Insulin Therapy in Type 2 Diabetes (1) Improvement in insulin sensitivityImprovement in insulin sensitivity

Intensive insulin therapy for up to Intensive insulin therapy for up to 4 4 weeksweeks actually improves insulin actually improves insulin sensitivity as measured by glucose-sensitivity as measured by glucose-insulin clamp method presumably due to insulin clamp method presumably due to reduced glucose toxicityreduced glucose toxicity

64

Disadvantages of Insulin Therapy in Type 2 Diabetes HypoglycemiaHypoglycemia

Weight gainWeight gain

Patient compliance and inconveniencePatient compliance and inconvenience

65

Patient Compliance and Inconvenience Pain Pain

Pens with smaller and finer needlesPens with smaller and finer needles Discrete modes of administrationDiscrete modes of administration

InconvenienceInconvenience Less invasive glucose monitoring system Less invasive glucose monitoring system

like the glucowatch and MiniMed like the glucowatch and MiniMed Continuous Monitoring systemContinuous Monitoring system

66

Insulin Preparation

Rapid-acting insulin, short-acting Rapid-acting insulin, short-acting preparations, long-acting insulins and ultra-preparations, long-acting insulins and ultra-long-acting insulinslong-acting insulins

The The site of insulin injection should be kept site of insulin injection should be kept constantconstant, because changing sits can change , because changing sits can change the pharmacokinetics, also, absorption can the pharmacokinetics, also, absorption can be highly variable, especially if be highly variable, especially if lipohypertrophy is presentlipohypertrophy is present

67

Monitoring Insulin Therapy (1) Home glucose monitoring (HGM)Home glucose monitoring (HGM) Monitoring should normally coincide with the Monitoring should normally coincide with the

peak of a particular type of insulin (e.g. peak of a particular type of insulin (e.g. 1-3 1-3 hours after RI and 6-8 hours after NPHhours after RI and 6-8 hours after NPH) to ) to evaluate the efficacy of the dose and to avoid evaluate the efficacy of the dose and to avoid hypoglycemiahypoglycemia

Initially, check blood glucose level before Initially, check blood glucose level before meals, 2 hours after meals at bedtime, and meals, 2 hours after meals at bedtime, and occasionally at 3:00AMoccasionally at 3:00AM

68

Monitoring Insulin Therapy (2)

Nonpharmacologic toolsNonpharmacologic tools can be used to can be used to control excessive glucose levelscontrol excessive glucose levelsInterval between the insulin injection Interval between the insulin injection

and mealtime can be increased to allow and mealtime can be increased to allow sufficient time for insulin to become sufficient time for insulin to become activeactive

Consuming fewer caloriesConsuming fewer calories

69

Monitoring Insulin Therapy (2)

Eliminating foods that cause rapid Eliminating foods that cause rapid increases in blood glucoseincreases in blood glucose

Spreading the calories over an Spreading the calories over an extended period of timeextended period of time

Exercising lightly after mealExercising lightly after meal

70

Addition of Insulin to oral Agents (1) Fasting blood glucose contributes more to daytime Fasting blood glucose contributes more to daytime

hyperglycemiahyperglycemia than do postpraandial changes than do postpraandial changes Fasting blood glucose concentration is highly Fasting blood glucose concentration is highly

correlated with the degree of hepatic glucose correlated with the degree of hepatic glucose production during the early morning hoursproduction during the early morning hours

Hepatic glucose output is directly decreased by Hepatic glucose output is directly decreased by insulin insulin and is indirectly inhibited by the ability of and is indirectly inhibited by the ability of insulin to reduce adipose tissue lipolysis, with lower insulin to reduce adipose tissue lipolysis, with lower concentrations of free fatty acids and gluconeogenesisconcentrations of free fatty acids and gluconeogenesis

71

Addition of Insulin to oral Agents (2) The peak action of intermediate-acting The peak action of intermediate-acting

insulin taken at bedtime also insulin taken at bedtime also coincides with coincides with the onset of the dawn phenomenonthe onset of the dawn phenomenon (early (early morning resistance to insulin caused by morning resistance to insulin caused by diurnal variations in growth hormone and diurnal variations in growth hormone and possible by norepinephrine levels)possible by norepinephrine levels)

Reduce the postbreakfast glucoseReduce the postbreakfast glucose in in addition to the fasting valueaddition to the fasting value

72

Insulin Treatment Strategies

Addition of Insulin to oral AgentsAddition of Insulin to oral Agents Sulfonylurea plus Evening NPHSulfonylurea plus Evening NPH Sulfonylurea plus Bedtime NPHSulfonylurea plus Bedtime NPH Sulfonylurea plus Evening 70/30 InsulinSulfonylurea plus Evening 70/30 Insulin Sulfonylurea plus Various Insulin RegimesSulfonylurea plus Various Insulin Regimes Sulfonylurea plus Lispro InsulinSulfonylurea plus Lispro Insulin Sulfonylurea plus Metformin plus InsulinSulfonylurea plus Metformin plus Insulin

73

Selection of Patients ObeseObese Overt diabetes for less than 10 to 15 yearsOvert diabetes for less than 10 to 15 years Diagnosed with type 2 diabetes after age Diagnosed with type 2 diabetes after age

of 35 yearsof 35 years Do not have FBG consistently over 250-Do not have FBG consistently over 250-

300 mg/dL300 mg/dL Have evidence of endogenous insulin Have evidence of endogenous insulin

secretory abilitysecretory ability

74

Dose Culculation

Divide the average FBG by 18Divide the average FBG by 18 Divided the body weight in kg by 10Divided the body weight in kg by 10

75

Start Insulin Therapy in Patients failing OAA Continue OAA at same dosage( eventually reduce)Continue OAA at same dosage( eventually reduce) Add single evening insulin doseAdd single evening insulin dose

ForFor thin thin patients (BMI < 25 kg/m2) – patients (BMI < 25 kg/m2) – 5 to10 u NPH5 to10 u NPH (bedtime)(bedtime)

ForFor obese obese patients (BMI > 25 kg/m2) – patients (BMI > 25 kg/m2) – 10 to 15 u NPH10 to 15 u NPH (bedtime) or 70/30 (before dinner)(bedtime) or 70/30 (before dinner)

Adjust dose by fasting self-monitored blood glucose (goal: Adjust dose by fasting self-monitored blood glucose (goal: 80-120 mg//dL)80-120 mg//dL)

Increase insulin dose weekly as neededIncrease insulin dose weekly as needed Increase by Increase by 4 units4 units if if FBG > 140 mg/dLFBG > 140 mg/dL Increase by Increase by 2 units2 units if if FBG = 120-140 mg/dLFBG = 120-140 mg/dL

76

Best time to give the evening injection of NPH between 10 PM and midnightbetween 10 PM and midnight

77

Dose Adjustment

If the daytime blood glucose concentrations If the daytime blood glucose concentrations start to become excessively start to become excessively lowlow, , the dose of oral the dose of oral medication must be reducedmedication must be reduced

If the prelunch and predinner blood glucose If the prelunch and predinner blood glucose remain excessively remain excessively highhigh, , In the past, a more In the past, a more conventional two-conventional two-

injection/day insulin regimeninjection/day insulin regimen has been used, has been used, discontinuing therapy with OAAdiscontinuing therapy with OAA

Now, Now, the use of insulin-sensitizing agentsthe use of insulin-sensitizing agents (metformin and the glitazones)(metformin and the glitazones)

78

Practical Strategy to Implement a Multi-Injection Insulin Regimens

Dose CalculationDose Calculation Split-mixed regimen in obese patients uses 70/30 Split-mixed regimen in obese patients uses 70/30

premixed insulin with an premixed insulin with an initial total daily dose (0.4-initial total daily dose (0.4-0.8 u/kg) equally0.8 u/kg) equally split between the prebreakfast and split between the prebreakfast and predinner mealspredinner meals

Lower doses (total daily dose 0.2-0.5 u/kg) in thin Lower doses (total daily dose 0.2-0.5 u/kg) in thin patientspatients

Dose AdjustmentDose Adjustment Dose is increased by 2-4 u increment every 3-4 days Dose is increased by 2-4 u increment every 3-4 days

until the morning FPG and predinner blood glucose until the morning FPG and predinner blood glucose concentration are consistently in the range of 80-120 concentration are consistently in the range of 80-120 mg/dLmg/dL

79

Addition of Oral Agents to Insulin

Insulin plus MetforminInsulin plus Metformin Inuslin plus GlitazonesInuslin plus Glitazones Insulin plus AcarboseInsulin plus Acarbose

80

Insulin Aspart/Lispro

Ultra-short-acting insulin analoguesUltra-short-acting insulin analogues Controls postprandial glucose excursions Controls postprandial glucose excursions Compared with regular human insulin:Compared with regular human insulin:

Reduces incidence of hypoglycemiaReduces incidence of hypoglycemia Questionable improvement in HbAQuestionable improvement in HbA1c1c

Thorsby P et al. European Association for the Study of Diabetes 1999. Abstract 57Home PD, et al. European Association for the Study of Diabetes 1999. Abstract 60

83

Etiology

During pregnancy, the placenta is secreting During pregnancy, the placenta is secreting diabetogenic hormones, which increase diabetogenic hormones, which increase insulin productioninsulin production growth hormonegrowth hormone corticotropin releasing hormonecorticotropin releasing hormone human placental lactogenhuman placental lactogen progesteroneprogesterone

84

Etiology

GDM occurs when the woman’s pancreas GDM occurs when the woman’s pancreas can not function sufficiently to overcome can not function sufficiently to overcome her relative insulin resistance and her relative insulin resistance and increased fuel consumptionincreased fuel consumption

GDM defined by ACOG as GDM defined by ACOG as “carbohydrate intolerance first “carbohydrate intolerance first recognized during pregnancy”recognized during pregnancy”

85

Risk Factors for GDM

family history family history pre-pregnancy weight of 110% of ideal pre-pregnancy weight of 110% of ideal

body weight body weight age >25 years oldage >25 years old previous history of large baby (9 lbs.)previous history of large baby (9 lbs.)

86

Risk Factors

history of abnormal glucose tolerancehistory of abnormal glucose tolerance ethnic group with higher incidence of ethnic group with higher incidence of

Diabetes Mellitus Type 2Diabetes Mellitus Type 2 previous unexplained perinatal loss or previous unexplained perinatal loss or

malformed childmalformed child mother was large at birthmother was large at birth

87

GDM associated with increased incidence of:

PreeclampsiaPreeclampsia HydramniosHydramnios Fetal macrosomiaFetal macrosomia Birth traumaBirth trauma Operative deliveriesOperative deliveries Later development of DM in motherLater development of DM in mother

88

GLOBAL SCREENING

SELECTIVE SCREENING

OR ?

89

Screening

SelectiveSelective suggested by ADA suggested by ADA

UniversalUniversal done at 24-28 weeks in all womendone at 24-28 weeks in all women may do earlier if suspiciousmay do earlier if suspicious

90

LOW RISK GROUP

Member of an ethnic group with a low Member of an ethnic group with a low prevalence of GDM.prevalence of GDM.

No known diabetes in first-degree relatives.No known diabetes in first-degree relatives. Age < 25 years.Age < 25 years. Weight normal before pregnancy.Weight normal before pregnancy. No history of abnormal glucose metabolism.No history of abnormal glucose metabolism. No history of poor obstetric outcome.No history of poor obstetric outcome.

91

Screening Test

*1-h PG (50gr) At 24-28 WK

PG > 140mg /dl

PG < 140mg / dl

*Fasting is not required.

92

PG > 140 mg/dl

*Perform 3-GTT (100g)

Definitive test

*Overnight fast of at least 8h but not more than 14h is required.

93

NDDG Criteria For GTT

TimeTime Venous plasmaVenous plasma

FastingFasting 105 mg/dl105 mg/dl

1 hour1 hour 190 mg/dl190 mg/dl



*If two values are met or exceeded, GDM is diagnosed

94

*New Criteria

TimeTime mg/dlmg/dl

FastingFasting 9595

1h1h 180180

2h2h 155155

3h3h 140140

* By carpenter & coustan.

95

PG < 140mg/dl

Non- diabetic

Repeat screening test if glycosuria,toxemia or hydramnios

develops,if fetus is large at 32 WK,or if maternal age >33 years,or if maternal

weight >120% IBW

96

Blood glucose goals

FastingFasting 65-85 mg/dl65-85 mg/dl

1-h postprandial1-h postprandial 140-150 mg/dl140-150 mg/dl

2-h postprandial2-h postprandial 120-130 mg/dl120-130 mg/dl

97

*Fasting < 90mg/dl

Institute calculated diet . Monitor FBS & 1 hr PC.

1 hr PC < 120 mg/dl

Continue diet

*During GTT

98

*Fasting > 90 mg/dl **1 hr PC > 120 mg/dl

Hospitalized patient to initiate insulin or use intensive outpatient program

* During GTT

** After short term diet trial.

99

Management

Metabolic controlMetabolic control DietDiet MedicationMedication

Fetal evaluationFetal evaluation Delivery considerationsDelivery considerations Post-partumPost-partum

100

Diet

Current Weight in relation to Ideal Body Weight

Daily Caloric Intake (kcal/kg)

<80% 35-40

80-120% 30

120-150% 24

>150% 12-15

101

Recommended Daily Caloric Intake

Prepregnancy Prepregnancy weight statusweight status

Kcal/kg/dKcal/kg/d Recommended Recommended weight gain (kg)weight gain (kg)

Desirable body Desirable body weightweight

3030 11-1611-16

>120% desirable >120% desirable body weightbody weight

2424 77

<80% desirable <80% desirable body weight body weight

36 to 4036 to 40 1818

102

*Daily caloric distribution

mealmeal Calories (%)Calories (%)

BreakfastBreakfast 10-15(%33 CHO)10-15(%33 CHO)

SnackSnack 0-100-10

LunchLunch 20-30(%45 CHO)20-30(%45 CHO)

SnackSnack 0-100-10

DinnerDinner 30-40(%40 CHO)30-40(%40 CHO)

SnackSnack 0-100-10

40% to %50 CHO,%20 protein, %30 fat

*Avoid fasting in excess of 4 to 5 h during the waking hours.

103

INSULIN PROTOCOLE

104

Total insulinTotal insulin Time(WK)Time(WK)

0.7u/kg0.7u/kg 6-186-18

0.8u/kg0.8u/kg 18-2618-26

0.9u/kg0.9u/kg 26-3626-36

1.0u/kg1.0u/kg 36-4036-40

*Insulin Requirement

* Initial calculation.

105

*FBS > 90mg/dl

NPH 0.15u/kg (Bedtime)

*Normal postprandial blood sugar.

106

*Postprandial Blood Glucose

Regular Insulin

1.5u/10gr CHO (prebreakfast)

1.0u/ 10gr CHO (prelunch & dinner)

* Normal FBS.

107

FBS & *PP

Regular , %55 of total dose

NPH , %45 of total dose

* Postprandial

108

NPH Regular

%30 prebreakfast

%15 bedtime

%22 prebreakfast

% 16.5 perlunch

%16.5 predinner

+

109

Monitoring of diabetic control

SMBG(*at least 4 times/day ) SMBG(*at least 4 times/day ) Hb A1C every 4 to 6 WK (in pregestational DM ).Hb A1C every 4 to 6 WK (in pregestational DM ). Urinary ketone (every morning & if BG>150).Urinary ketone (every morning & if BG>150).

*premeal, bedtime & twice weekly 1h pp.

110

Postprtum course of the GDM

%98 of all gestational diabetic women %98 of all gestational diabetic women revert to normoglycemia postpartum.revert to normoglycemia postpartum.

Probability that DM will recur in each Probability that DM will recur in each subsequent pregnancy is about %90.subsequent pregnancy is about %90.

There is %60 chance of manifesting There is %60 chance of manifesting DM within 20 years.DM within 20 years.

111

At 6-12 WK postpartum all patient who had GDM should be reclassified

FBS mg/dlFBS mg/dl DiagnosisDiagnosis

> 126(on two > 126(on two occasions)occasions)

DMDM

110-125110-125Impaired fasting Impaired fasting

glucoseglucose

< 110< 110 NormalNormal

Incretin therapies

Incretin therapies

Physiologic defects associated with Type 2 diabetesPhysiologic defects associated with Type 2 diabetes

ββ-Cell dysfunction-Cell dysfunction

Inadequate insulin secretion and glucagon Inadequate insulin secretion and glucagon over-secretionover-secretion

The role of incretins in normal physiologyThe role of incretins in normal physiology

Approaches to incretin therapyApproaches to incretin therapy

GLP-1 analoguesGLP-1 analogues

DPP-4 inhibitorsDPP-4 inhibitors

DPP-4=dipeptidyl peptidase-4GLP-1=glucagon-like peptide-1

Islet β-cell function (HOMA %B) in the UKPDS

HOMA=homeostasis model assessment; UKPDS=United Kingdom Prospective Diabetes StudyUKPDS Group. Diabetes. 1995

Conservative(primarily diet)

Islet β-cell function (%)

100

80

60

40

20

0

Non-overweight Overweight

0 1 2 3 4 5 6 0 1 2 3 4 5 6

Sulfonylurea

Metformin

Loss ~4% per year

Years from randomization

Kemp et al. Rev Endocr Metab Disord. 2003

Nestin-positive intra-islet progenitor

Duct-derived progenitor

Undifferentiated cells Differentiated cells

α-Cell

β-Cell

Duct cell

Activin ABetacellulinHepatocyte growth factorGLP-1GLP-1

Pancreatic duct

Lumen

Neogenesis(birth)

Apoptosis(death)

30–40 days

β-Cell mass is sustained by continual birth and death of cells by neogenesis and apoptosis

GLP-1GLP-1

β-Cell mass in Type 2 diabetes

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

ND IFG T2DM ND T2DM

-C

ell

volu

me

(%)

Obese Lean

-50%-50%

-63%-63%

Butler et al. Diabetes. 2003ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus

Excessive hepatic glucose production in Excessive hepatic glucose production in Type 2 diabetesType 2 diabetes

Plasma glucose concentration

Fasting & Fasting & postprandial postprandial

hyperglycaemiahyperglycaemia

Insulin; IR

GlucagonHepaticglucoseoutput

IR=insulin resistance

-60 0 60 120 180 240

20.018.316.615.013.36.14.4

14013012011010090

1209060300

Glucose (mmol/l)

Insulin (mU/l)

Glucagon (ng/l)

Meal

Time (min)

Type 2 diabetes

Normal subjects

Delayed/depressedinsulin response

Müller et al. N Engl J Med. 1970

Nonsuppressed glucagon

Normal subects n=11; Type 2 diabetes n=12

Insulin and glucagon dynamics in response to meals in normal subjects and Type 2 diabetes

Action of glucagon

Low blood glucose promotes Low blood glucose promotes glucagon release from glucagon release from --cells of pancreascells of pancreas Glycogen Glucose

Glucagon stimulatesGlucagon stimulatesbreakdown of glycogenbreakdown of glycogen

Raises blood glucose

β-Cell function and glucagon in Type 2 diabetes

• Loss of β-cell function and glucagon over-secretion both play key roles in Type 2 diabetes development

• Progressive β-cell decline is coupled with inadequate insulin secretion

• Glucagon is not suppressed during the postprandial period

• Hepatic glucose production is increased during the fasting period and is not suppressed during the postprandial period

Incretin therapies


ββ-cell dysfunction-cell dysfunction

Inadequate insulin secretion and glucagon Inadequate insulin secretion and glucagon over-secretionover-secretion





GLP-1: effects in humans

GLP-1 is secreted fromL-cells of the jejunum

and ileum

That in turn…

• Stimulates glucose- dependent insulin secretion

• Suppresses glucagonsecretion

• Slows gastric emptying

Long-term effectsin animal models:

• Increase of β-cell mass and improved β-cell function

• Improves insulin sensitivity

• Leads to a reduction offood intake

After food ingestion…

Drucker. Curr Pharm Des. 2001Drucker. Mol Endocrinol. 2003

Nauck et al. Diabetologia. 1986

Incretin effect on insulin secretionIncretin effect on insulin secretion

Oral glucose loadIntravenous glucose infusion

Time (min)In

suli

n (m

U/l

)

80

60

40

20

018060 1200

Time (min)

Insu

lin

(mU

/l)

80

60

40

20

018060 1200

Incretin effect

Control subjects (n=8) People with Type 2 diabetes (n=14)

• GLP-1 and GIP are the major incretin gut hormones released GLP-1 and GIP are the major incretin gut hormones released in response to food ingestionin response to food ingestion

• GLP-1 and GIP enhance insulin secretion from GLP-1 and GIP enhance insulin secretion from ββ--cells in a cells in a glucose-dependent mannerglucose-dependent manner

• GLP-1 suppresses glucagon release fromGLP-1 suppresses glucagon release fromαα--cells in a glucose-dependent mannercells in a glucose-dependent manner

• The incretin effect is attributed to intestinal derived factors, The incretin effect is attributed to intestinal derived factors, GLP-1 and GIPGLP-1 and GIP

• The incretin effect is diminished in Type 2 diabetesThe incretin effect is diminished in Type 2 diabetes• GIP is not a therapeutic target: although its levels are normal GIP is not a therapeutic target: although its levels are normal

in Type 2 diabetes, GIP is functionally ineffective in Type 2 diabetes, GIP is functionally ineffective

Summary of the incretin effectSummary of the incretin effect

GIP=glucose-dependent insulinotropic peptide

Incretin therapies


ββ-cell dysfunction-cell dysfunction

Inadequate insulin secretion and glucagonInadequate insulin secretion and glucagonover-secretionover-secretion





Degradation of GLP-1

1 2 3 30

GLP-1

Des-HA-GLP-1 (inactive)

Enzymatic cleavage of GLP-1 by DPP-4 inactivates GLP-1

1 2 3 30

DPP-4

Two possible solutions to utilize GLP-1 action therapeutically:

1) Long-acting DPP-4-resistant GLP-1 analogues / incretin mimetics2) DPP-4 inhibitors / incretin enhancers

Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994

GLP-1 enhancement

Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

GLP-1 secretion is impaired in Type 2 diabetes

Natural GLP-1 has extremely short half-life

Add GLP-1 analogues with longer half-life:

• exenatide

• liraglutide

Injectables

Block DPP-4, the enzyme that degrades GLP-1:

• sitagliptin

• vildagliptin

Oral agents

Active GLP-1

Inactive GLP-1

Diagram of how DPP-4 inhibition might be expected to Diagram of how DPP-4 inhibition might be expected to improve blood glucose controlimprove blood glucose control

Increase insulin secretionDecrease glucagon release

Glucose control

DPP-4 DPP-4 inhibitorX

Increase insulin secretionDecrease glucagon release

Glucose control improved

Inactive GLP-1

Active GLP-1

Incretin mimetics and DPP-4 inhibitors:major differences

Properties/effect Incretin mimetics DPP-4 inhibitors

Mechanism of stimulation of insulin secretion exclusively through GLP-1 effect

Yes Unknown

Restitution of insulin secretion (2 phases) Yes (exenatide) Yes

Hypoglycaemia No No

Maintained counter-regulation by glucagon in hypoglycaemia

Yes Not tested

Inhibition of gastric emptying Yes Marginal

Effect on body weight Weight loss Weight neutral

Side effects Nausea None observed

Administration Subcutaneous Oral

Gallwitz. Eur Endocr Dis. 2006

1 sulfonylureas reduce fasting and ppg should be initiated at low doses increased at 1- to 2-week...

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