![Page 1: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/1.jpg)
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
![Page 2: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/2.jpg)
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.
![Page 3: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/3.jpg)
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.
![Page 4: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/4.jpg)
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
![Page 5: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/5.jpg)
6
Sulfonylureas Some sulfonylureas have significant drug
interactions with other medications such as Alcohol Warfarin Aspirin ketoconazole a-glucosidase inhibitors Fluconazol
![Page 6: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/6.jpg)
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
![Page 7: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/7.jpg)
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.
![Page 8: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/8.jpg)
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
![Page 9: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/9.jpg)
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.
![Page 10: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/10.jpg)
13
Metformin
Metformin should be discontinued in patients
Who are seriously ill
Patients who can take nothing orally
Those receiving radiographic contrast
![Page 11: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/11.jpg)
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
![Page 12: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/12.jpg)
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
![Page 13: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/13.jpg)
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.
![Page 14: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/14.jpg)
17
a-GLUCOSIDASE INHIBITORS
These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen.
![Page 15: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/15.jpg)
18
a-GLUCOSIDASE INHIBITORS
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).
![Page 16: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/16.jpg)
19
a-GLUCOSIDASE INHIBITORS
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.
![Page 17: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/17.jpg)
20
a-GLUCOSIDASE INHIBITORS
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 .
![Page 18: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/18.jpg)
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.
![Page 19: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/19.jpg)
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%))
![Page 20: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/20.jpg)
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
![Page 21: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/21.jpg)
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
![Page 22: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/22.jpg)
26
Rosiglitazone
N N
CH3
OS
NH
O
O
Pioglitazone
N
CH3 CH2
OS
NH
O
O
Thiazolidinediones: Structures
Treating to Target
![Page 23: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/23.jpg)
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
![Page 24: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/24.jpg)
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
![Page 25: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/25.jpg)
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
![Page 26: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/26.jpg)
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
![Page 27: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/27.jpg)
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
![Page 28: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/28.jpg)
32
INSULIN THERAPY IN TYPE 2 DM
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).
![Page 29: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/29.jpg)
33
![Page 30: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/30.jpg)
34
INSULIN THERAPY IN TYPE 2 DM
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.
![Page 31: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/31.jpg)
35
INSULIN THERAPY IN TYPE 2 DM
Both morning and bedtime intermediate insulin may be used in combination with oral glucose-lowering agents (biguanides, a-glucosidase inhibitors, or thiazolidinediones).
![Page 32: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/32.jpg)
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
![Page 33: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/33.jpg)
37
CHOICE OF INITIAL GLUCOSE-LOWERING AGENT
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.
![Page 34: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/34.jpg)
38
CHOICE OF INITIAL GLUCOSE-LOWERING AGENT
Some physicians begin insulin in individuals with severe hyperglycemia [fasting glucose > 250 to 300 mg/dL].
![Page 35: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/35.jpg)
39
CHOICE OF INITIAL GLUCOSE-LOWERING AGENT
Insulin secretagogues biguanidesa-glucosidase inhibitors thiazolidinediones insulin are approved for monotherapy
of type 2 .
![Page 36: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/36.jpg)
40
CHOICE OF INITIAL GLUCOSE-LOWERING AGENT
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
![Page 37: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/37.jpg)
41
CHOICE OF INITIAL GLUCOSE-LOWERING AGENT
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
![Page 38: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/38.jpg)
42
CHOICE OF INITIAL GLUCOSE-LOWERING AGENT
Biguanides a-glucosidase inhibitors TZD
do not directly cause hypoglycemia
![Page 39: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/39.jpg)
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
![Page 40: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/40.jpg)
44
![Page 41: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/41.jpg)
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
![Page 42: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/42.jpg)
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
![Page 43: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/43.jpg)
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
![Page 44: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/44.jpg)
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
![Page 45: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/45.jpg)
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
![Page 46: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/46.jpg)
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
![Page 47: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/47.jpg)
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
![Page 48: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/48.jpg)
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
![Page 49: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/49.jpg)
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
![Page 50: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/50.jpg)
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
![Page 51: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/51.jpg)
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
![Page 52: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/52.jpg)
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
![Page 53: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/53.jpg)
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
![Page 54: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/54.jpg)
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
![Page 55: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/55.jpg)
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
![Page 56: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/56.jpg)
64
Disadvantages of Insulin Therapy in Type 2 Diabetes HypoglycemiaHypoglycemia
Weight gainWeight gain
Patient compliance and inconveniencePatient compliance and inconvenience
![Page 57: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/57.jpg)
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
![Page 58: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/58.jpg)
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
![Page 59: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/59.jpg)
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
![Page 60: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/60.jpg)
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
![Page 61: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/61.jpg)
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
![Page 62: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/62.jpg)
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
![Page 63: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/63.jpg)
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
![Page 64: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/64.jpg)
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
![Page 65: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/65.jpg)
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
![Page 66: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/66.jpg)
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
![Page 67: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/67.jpg)
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
![Page 68: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/68.jpg)
76
Best time to give the evening injection of NPH between 10 PM and midnightbetween 10 PM and midnight
![Page 69: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/69.jpg)
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)
![Page 70: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/70.jpg)
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
![Page 71: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/71.jpg)
79
Addition of Oral Agents to Insulin
Insulin plus MetforminInsulin plus Metformin Inuslin plus GlitazonesInuslin plus Glitazones Insulin plus AcarboseInsulin plus Acarbose
![Page 72: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/72.jpg)
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
![Page 73: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/73.jpg)
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
![Page 74: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/74.jpg)
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”
![Page 75: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/75.jpg)
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.)
![Page 76: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/76.jpg)
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
![Page 77: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/77.jpg)
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
![Page 78: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/78.jpg)
88
GLOBAL SCREENING
SELECTIVE SCREENING
OR ?
![Page 79: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/79.jpg)
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
![Page 80: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/80.jpg)
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.
![Page 81: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/81.jpg)
91
Screening Test
*1-h PG (50gr) At 24-28 WK
PG > 140mg /dl
PG < 140mg / dl
*Fasting is not required.
![Page 82: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/82.jpg)
92
PG > 140 mg/dl
*Perform 3-GTT (100g)
Definitive test
*Overnight fast of at least 8h but not more than 14h is required.
![Page 83: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/83.jpg)
93
NDDG Criteria For GTT
TimeTime Venous plasmaVenous plasma
FastingFasting 105 mg/dl105 mg/dl
1 hour1 hour 190 mg/dl190 mg/dl
2 hour2 hour 165 mg/dl165 mg/dl
3 hour3 hour 145 mg/dl145 mg/dl
*If two values are met or exceeded, GDM is diagnosed
![Page 84: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/84.jpg)
94
*New Criteria
TimeTime mg/dlmg/dl
FastingFasting 9595
1h1h 180180
2h2h 155155
3h3h 140140
* By carpenter & coustan.
![Page 85: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/85.jpg)
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
![Page 86: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/86.jpg)
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
![Page 87: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/87.jpg)
97
*Fasting < 90mg/dl
Institute calculated diet . Monitor FBS & 1 hr PC.
1 hr PC < 120 mg/dl
Continue diet
*During GTT
![Page 88: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/88.jpg)
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.
![Page 89: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/89.jpg)
99
Management
Metabolic controlMetabolic control DietDiet MedicationMedication
Fetal evaluationFetal evaluation Delivery considerationsDelivery considerations Post-partumPost-partum
![Page 90: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/90.jpg)
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
![Page 91: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/91.jpg)
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
![Page 92: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/92.jpg)
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.
![Page 93: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/93.jpg)
103
INSULIN PROTOCOLE
![Page 94: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/94.jpg)
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.
![Page 95: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/95.jpg)
105
*FBS > 90mg/dl
NPH 0.15u/kg (Bedtime)
*Normal postprandial blood sugar.
![Page 96: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/96.jpg)
106
*Postprandial Blood Glucose
Regular Insulin
1.5u/10gr CHO (prebreakfast)
1.0u/ 10gr CHO (prelunch & dinner)
* Normal FBS.
![Page 97: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/97.jpg)
107
FBS & *PP
Regular , %55 of total dose
NPH , %45 of total dose
* Postprandial
![Page 98: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/98.jpg)
108
NPH Regular
%30 prebreakfast
%15 bedtime
%22 prebreakfast
% 16.5 perlunch
%16.5 predinner
+
![Page 99: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/99.jpg)
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.
![Page 100: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/100.jpg)
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.
![Page 101: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/101.jpg)
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
![Page 102: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/102.jpg)
112
![Page 103: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/103.jpg)
Incretin therapies
![Page 104: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/104.jpg)
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
![Page 105: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/105.jpg)
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
![Page 106: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/106.jpg)
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
![Page 107: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/107.jpg)
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
![Page 108: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/108.jpg)
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
![Page 109: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/109.jpg)
-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
![Page 110: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/110.jpg)
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
![Page 111: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/111.jpg)
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
![Page 112: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/112.jpg)
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
![Page 113: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/113.jpg)
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
![Page 114: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/114.jpg)
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)
![Page 115: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/115.jpg)
• 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
![Page 116: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/116.jpg)
Incretin therapies
Physiologic defects associated with Type 2 diabetesPhysiologic defects associated with Type 2 diabetes
ββ-cell dysfunction-cell dysfunction
Inadequate insulin secretion and glucagonInadequate insulin secretion and glucagonover-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
![Page 117: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/117.jpg)
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
![Page 118: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/118.jpg)
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
![Page 119: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/119.jpg)
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
![Page 120: 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](https://reader037.vdocuments.us/reader037/viewer/2022110209/56649e0b5503460f94af3f76/html5/thumbnails/120.jpg)
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