Updated for Diabetes Mellitus

Krairat Komdee, MD.Department of Internal Medicine

Phayao Hospital

Outline

ClassificationScreeningDiagnosisEvaluationManagement

Diabetes mellitus

A group of metabolic diseases characterized by hyperglycemia

Resulting from defects in insulin secretion, insulin action, or both

The chronic hyperglycemia of diabetes is ass. with dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels

Classification

Type 1 diabetes mellitus (5-10%) ß-cell destruction, usually leading to

absolute insulin deficiency; immune mediated, idiopathic

Juvenile onset, IDDM, type I Auto-immune disease Pancreas is unable to produce insulin Generally diagnosed from birth to age 30,

highest incidence between 12-18 years of age

Classification

Type 2 diabetes mellitus (90-95%) may range from predominantly insulin

resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance

Adult onset, NIDDM, type II Disorder ass. with obese and aging process Generally diagnosed after age 40

Classification

Other specific type ( <1%) Genetic defects of B-cell funtion; MODY Genetic defects in insulin action Disease of the exocrine pancreas Endocrinopathies Drug- or chemical-induced Infections Other genetic syndrome sometimes ass. With diabetes;

Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, Wolfran’s syndrome

Gestational diabetes mellitus (GDM) Hyperglycemia 1st diagnosed in pregnancy Diagnosis made by OGTT

Risk Factors of Developing Diabetes

Family history; 1st degree relative with diabetes Physical inactivity Previous IGT or IFG = Impaired glucose

homeostasis Previous GDM or baby > 4 kg Hypertension ; BP ≥ 140/90 mm.Hg HDL ≤ 35mg/dl, TG ≥ 250mg/dl Overweight or obese Polycystic ovary syndrome; PCOS Acanthosis nigricans History of vascular disease Sedentary lifestyle

Screening of Diabetes in adult

Indication:1. Age ≥ 45 years old esp. BMI ≥ 25kg/m2

(if normal, then repeat q 3 years)2. Asymptomatic and BMI ≥ 25kg/m2 with

risks of having diabetes (if normal, then repeat q 1-2 years)

Criteria for diagnosis of diabetes

FPG ≥ 126 mg/dl. Fasting is defined as no caloric intake for at least 8 h

Symptoms of hyperglycemia and a casual plasma glucose ≥ 200 mg/dl. Casual is defined as any time of day without regard to

time since last meal The classic symptoms of hyperglycemia include

polyuria, polydipsia, and unexplained weight loss. 2-h plasma glucose ≥ 200 mg/dl during an OGTT

Using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water

Diagnosis of Diabetes

Fasting 2-hour(after 75-glucose)

Normal < 100 < 140

IGT < 126 140-199

IFG 100 - 125 <140

DM ≥ 126 ≥ 200

2 or more abnormal values are required for diagnosis

AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13(Suppl 1) 2007

IGT VS IFG

Impaired glucose tolerance

Impaired fasting glucose

Impaired Fasting Glucose

FPG ‹ 100 mg/dl Normal fasting glucose

FPG 100–125 mg/dl IFG

FPG ≥ 126 mg/dl Provisional diagnosis of diabetes For diagnosis must be confirmed

Oral Glucose Tolerance Test

2-h postload glucose ‹ 140 mg/dl Normal glucose tolerance

2-h postload glucose 140–199 mg/dl IGT ; impaired glucose tolerance

2-h postload glucose ≥ 200mg/dl

Type 1 and 2 DM : Clinical comparison

Features Type 1 Type 2

Age of onset < 20 30

Onset Sudden Gradual

Structure Thin Obese

Others DKA Diabetes in family

Lab : C-peptide testing with glucagon or mixed meal test

Gestational Diabetes Mellitus; GDM

Recommendations from the ADA use Carpenter/Coustan diagnostic criteria as well as the alternative use of a diagnostic 75-g 2-h OGTT

Human placentral lactogen increase insulin resistance

May normal after delivery or turn to DM type 2

Risk Factors for Gestational Diabetes Mellitus

>25 years of age Overweight or obese state Family history of diabetes mellitus (ie, in a irst-

degree relative) History of abnormal glucose metabolism History of poor obstetric outcome History of delivery of infant with a birth weight

>4kg History of polycystic ovary syndrome Latino/Hispanic, non–Hispanic black, Asian

American, Native American, or Paciic Islander ethnicity

Fasting (no energy intake for at least 8 hours) plasma glucose concentration >85 mg/dL or 2-hour

Postprandial glucose concentration >140 mg/dL (indicates need to perform a 75-g oral glucose tolerance test)

I/C for screening at 1st ANC

Family history of DMObeseHx of baby > 4000 gmAge > 35 yrsHx of perinatal deathGlucosuriaHypertensionMultiparityHx of GDMHx of recurrent abortionHx of congenital deformity

Screening

GCT 50 gms of glucose then CBG at 1hr if >

140mg/dl OGTTOGTT

NPO 10-12 hrs 100 gms of glucose Plasma glucose before 1hr then q 1 hr after

glucose ingestion x 3 times Positive more than 2 Dx

Diagnosis of GDM

State at plasma glucose measurement

Plasma glucose concentration; mg/dl

Fasting > 95 mg/dl

1-hour > 180

2-hour > 155

Two or more of the listed venous plasma glucose concentrations must be met or exceeded for a positive diagnosis. The test should be performed after an overnight fast of 8 to 14 hours and after at least 3 days of unrestricted diet (ie, ≥150 g carbohydrate per day) and unlimited physical activity

GDM vs DM before Pregnancy

20 wks of pregnancy Post-pandial hyperglycemia No chronic complication

Fasting hyperglycemia or pre-pandial hyperglycemia

Chronic complication

Maturity-Onset Diabetes of the Young; MODY

Age < 25AD; 3 generationNo sign or clinical of autoimmuneNo obesityInsulin secretion impairmentNo insulin resistance

Distinctive features of MODY

Transcription factor Extrapancreatic features

HNF1A (MODY 3) GlycosuriaRaised HDL

HNF1B (MODY 5) Renal cystsPKDRenal impairmentUterine and genital abnormalitiesHyperuricemiaShort stature

IPF-1 (MODY 4) Pancreatic agenesis with homozygous mutation

Correlation between A1C and mean plasma glucose levels

HbA1C Mean plasma glucose (mg/dl)

6 135

7 170

8 205

9 240

10 275

11 310

12 345

Prevention of Type 2 Diabetes Mellitus

Initiate interventions include lifestyle modiications : Weight reduction goal: 5% to 10% of total

body weight Nutrition goals:

• reduce fat intake to less than 30% of total energy intake

• reduce saturated fat intake to less than 10% of total energy intake

• increase fiber intake to 15 g/1000 kcalPrescribe regular physical activity (approx

150 min per wk)Counsel patients with prediabetes mellitus

about CV risk factors such as tobacco use, hypertension, and dyslipidemia

Management of Diabetes Mellitus

Standard of care for people with diabetes

Goal

Pre-prandial plasma glucose (mg/dl) < 110

Post-prandial plasma glucose < 140

HbA1C < 6.5 - 7%

Blood Pressure (mmHg) < 130/80

Lipids

LDL-cholesterol (mg/dl) < 100

Triglycerides < 150

HDL > 40

Anti-Diabetic Drug

Major Classes of Antidiabetic Drugs

1.Drugs that stimulate pancreas to make more insulin

SulfonylureasMeglitinides

2.Drugs that sensitize insulin action

ThiazolidinedionesBiguanides

3.Drugs that slow the absorption of starches

Alpha-glucosidase inhibitors

4.Drugs that enhance incretin effects

GLP-1 R agonistsDPP-IV inhibitor

5.Insulin

6.New drug atc at ECS Ribonamont

Lifestyle Modification (Medical Nutrition and Exercise)

If blood glucose targets not achieved within 3 months, move to Oral Agent Stage

Potential cumulative benefit: ~1 percentage point reduction in HbA1c

Combination Oral Agent StageCurrent therapy: Add Oral Agent: Sulfonylurea: Metformin, TZD, or basal insulinMetformin: Sulfonylurea, Repaglinide, TZD, or

basal insulinAlternative drugs: -GI or DPP-4 inhibitorConsider triple combination therapy (SU +

Metformin + Thaizolidenedione)

Combination Oral Agent and insulin StageMorning FPG >300 mg/dL: Continue OAS; add BT G

or NPotential cumulative benefit: 2-4 percentage point

reduction in HbA1c

HbA1C < 8% and/orFPG < 200 mg/dL

FPG 200-300 mg/dL

At Diagnosis

Oral hypoglycemic agent

Metformin Sulfonylurea

Insulin resistance (BMI >23, central obesity, BP >130/85 or on antiHTN, elevated TG, low HDL-C)

Insulin deficiency (BMI <23, severe hyperglycemia, postprandial hyperglycemia)

Alternative drugs; TZD or repaglinide or -GI or DPP-4 inhibitor

Potential cumulative benefit: ~2 percentage point reduction inHbA1c Any individual may have both insulin deficiency and insulin

resistance

FPG 250-350 mg/dL HbA1c > 9%

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Combination Oral Agent and insulin StageMorning FPG >300 mg/dL: Continue OAS; add BT G

or NPotentialc umulative benefit: 2-4 percentage point

reduction in HbA1c

Physiologic Insulin (4 Injections)Or refer to endocrinologist

RA – RA – RA - G or NOptional R – R – R – G or N

Begin single injection of G at bed time (alternatively at breakfast) or N at bedtime; and RA or R before meals as

needed based on patterns of elevated post-meal glucose values

Potential cumulative benefit: >4 percentage point reduction in HbA1c

Insulin Therapy (3 Injections) or refer to

endocrinologistIf persistent

midafternoon hyperglycemia , need more flexibility and/or

intensified insulin regimen, start

physiologic insulin Potentialc umulative

benefit: >4 percentage point reduction in HbA1c

Insulin Therapy (2 Injections)

RA/N –0-RA/N-0R/N-0-R/N-0

If persistent AM hyperglycemia or

nocturnal hypoglycemia, start insulin therapy (3

injections); if need more flexibility or intensified

regimen, start physiologic insulin

Potential cumulative benefit: >4 percentage

point reduction in HbA1c

Abbreviation for Insulin

RA=Rapid Acting(Lispro or Aspart)N=NPH

R=RegularG=GlargineO=None

Dose Schedule: AM-Midday-PM-hs RA – RA – RA – G

HbA1C >11% and/orFPG >300 mg/dL +

symptomatic hyperglycemia

Treat to Target

1. Target of treatment is HbA1c <7%2. Monthly improvement is SMBG of

15-30 mg/dl and/or HbA1c of 0.5-1.0 % is considered significant improvement.

3. Continue with lifestyle modification throughout all stages of therapy.

4. This Decision path is bi-directional; patients move in either direction between therapies.

5. Consider insulin sensitizers when insulin dose is > 0.7 U/kg.

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Algorithm for the metabolic management of type 2 DM

Lifestyle + Metformin+

Basal insulin

Lifestyle + Metformin+

sulfonylurea

At diagnosis: Lifestyle

+ Metformin

Lifestyle + Metformin

+Intensive insulin

Lifestyle + Metformin+

Pioglitazone No hypoglycemiaEdema/CHFBone loss

Lifestyle + Metformin+

GLP-1 agonistNo hypoglycemiaWeight lossNausea/vomiting

Lifestyle + Metformin

+Pioglitazone

+sulfonylurea

Lifestyle + Metformin

+Basal insulin

STEP 1 STEP 2 STEP 3

Consensus statement of ADA and EASD. Diabetes Care 2008;31:1-11

Pharmacologic Targets of Current Drugs Used in the Treatment of

T2DM

-glucosidase inhibitorsDelay intestinal carbohydrate absorption

ThiazolidinedionesDecrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle, decrease glucose production in liverSulfonylureas

Increase insulin secretion from pancreatic -cells

GLP-1 analogsImprove pancreatic islet glucose sensing, slow gastric emptying, improve satiety

BiguanidesIncrease glucose uptakeand decrease hepatic glucose production

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitusAdapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.Ahrén B, Foley JE. Int J Clin Pract. 2008; 62: 8–14.

GlinidesIncrease insulin secretion from pancreatic -cells

DPP-4 inhibitorsProlong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake

Oral Hypoglycemic Agents

SulfonylureaGlyburide/ Glibenclamide

1.23 – 5 mg od 20 mg divided to twice daily

Administer once daily doses with breakfast or first main mealDoses >10 mg/d should be divided and given twice daily

Glipizide 5 mg once daily; 2.5 mg once daily in elderly patients

40 mg in 2divided doses

Administer once daily doses 30 min before breakfast or after first main meal Doses >15 mg/d should be divided and given twice daily

Glimepiride (Amaryl)

1 to 2 mg once daily 8 mg once daily Administer with breakfast or first main meal

Action of Sulfonylureas

Oral Hypoglycemic Agent

Glinides (Short-Acting Secretagogues)Repaglinide Elderly patients and patients

not previously treated with hypoglycemic agents or patients with HbA1c <8%:Give 0.5 mg three times daily

Patients previously treated with hypoglycemic agents or those with HbA1c >8%: Give 1 to 2 mg three times daily

16 mg/d Administer 15 to 30 min before each meal

Oral Hypoglycemic Agent

α-Glucosidase Inhibitors

Acarbose (Precose)

25 mg three times daily

100 mg three times daily

Administer with first bite of each main meal

Dosage should be gradually increased as tolerated over several weeks

Biguanides

Metformin 500 mg twice daily or 850 mg once daily in the morning

2550 mg in 3 divided doses

Administer with meals

Maximum effective dose is 2000 mg/d

Oral Hypoglycemic Agent

Thiazolidinediones

Pioglitazone (Actos)

15 or 30 mg once daily

45 mg once daily

Administer with or without food

Rosiglitazone (Avandia)

4 mg once daily or 2 mg twice daily

8 mg once daily or 4 mg twice daily

Administer with or without food

New drugs for Treat DM

Considration for Oral Therapy in Patients with Type2 DM

Considration for Oral Therapy in Patients with Type2 DM

Effect of Oral Therapies on HbA1C Levels in Patients with DM

Anti-diabetic agents

Agent Advantages Disadvantages

Sulfonylureas Inexpensive, extensive experience

Weight gain, hypoglycemia

Repaglinide Reduce postprandial blood glucose, Lifestyle flexibility usable in renal failure; mild to moderate

Expensive, multiple daily dose, weight gain, long-tern efficacy/safety data lacking

Metformin CV benefit, improved multiple cardiovascular risk ,weight loss, low risk of hypoglycemia ,inexpensive

GI side effects, rare lactic acidosis

Glitazones More sustained glucose control, reduced macrovascular risk(pioglitazone only) , low risk of hypoglycemia, reduced atherosclerosis progression(PROACTIVE study), improve multiple CV risk, reduced microalbuminuria, Usable in renal failure

Expensive, weight gain, heart failure, peripheral edema, increase risk of distal fractures in women

Anti-diabetic agents

Agent Advantages Disadvantages

- glucosidase inhibitor

Weight neutral, low risk of hypoglycemia

GI side effects,multiple daily dose

Insulin Most effective Inconvenience, hypoglycemia

DDP-IV inhibitor

Weight neutral to weight loss, no hypoglycemia, usable for CKD

Expensive, possible link to pancreatitis

GLP-1 analog Weight loss, low risk of hypoglycemia

Expensive, subcutneous form inconvenience, possible link to pancreatitis

ECS blockage

Effect on multiple organ, improve CMR factor; no hypoglycemia, increase HDL, decrease LDL

Expensive, problem with psychiatric patient

Starting and adjustment of insulin

Start with bedtime intermediate-acting insulin or bedtime or morning long-acting insulin 10U or 0.2U/kg

Increase dose by 2U every 3 daysTarget FBG 70-130 mg/dl

If FBG 70-130 and HbA1C > 7%Check premeal and bedtime Blood glucose

High pre-lunch BGAdd rapid-acting insulin at breakfast

High pre-dinner BGAdd NPH at breakfastOr rapid-acting insulin at lunch

High pre-bedtime BGAdd rapid-acting insulin at dinner

Endocannabinoid system is a modulatory system

• Endocannabinoids:– Synthesized on demand

from lipid precursors in postsynaptic cell

– Activate CB1 receptors presynaptically, then degraded immediately

– Act as retrograde messengers

– Inhibit neurotransmitter release

• CB1 receptors:– Play a key role in energy

balance and lipid and glucose metabolism

Di Marzo V et al, 2005; Di Marzo V et al, 1998;Wilson R et al, 2002

Site of action Mechanism(s) Addresses

Hypothalamus / Nucleus accumbens

Food intakeBody weightIntra-abdominal adiposity

Adipose tissue Adiponectin Lipogenesis

DyslipidaemiaInsulin resistance

Muscle Glucose uptake Insulin resistance

Liver Lipogenesis Dyslipidaemia

Insulin resistance

GI tract Satiety signalsBody weightIntra-abdominal adiposity

Sites of CB1 receptors and potential effects of CB1 receptor blockade