Kathleen M. Dungan, MD Division of Endocrinology, Diabetes & - - PDF document

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Type 2 Diabetes in the Adult

A Collision Course

Kathleen M. Dungan, MD

Division of Endocrinology, Diabetes & Metabolism The Ohio State University

Prevalence of Diabetes by Age 2005

%

5 10 15 20 25 <20 >20 >60.9 % www.cdc.org

Incidence of Diabetes in the U.S.* Age 18-79 Years

www.cdc.org *per 1000 Population

If current trends continue, 1 in 3 Americans and 1 in 2 minorities born in 2000 will develop diabetes during their lifetime!

Obesity Trends* Among U.S. Adults BRFSS, 1990, 1998, 2006

( * BMI ≥3 0, or about 30 lbs. overw eight for 5’4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30% 1 9 9 8 2 0 0 6 1 9 9 0

www.cdc.gov

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The Toll of Diabetes

• 6th leading cause of death in the U.S.

Only 35% of patients have DM listed on certificate CAD and stroke account for 65% of deaths

• Leading cause of new blindness in adults
• Leading cause of renal failure
• Leading cause of non-traumatic lower limb

amputations

www.diabetes.org Cheng et al Diabetes Care 2008;31:279-284

Economic Costs 2007

Direct: $115 billion Indirect: $58.2 billion $174 billion

• $11,744 per patient/yr
• 1 in 5 healthcare dollars is spent on

patients with diabetes!

ADA; Diabetes Care 2008;31(3):1-20

Pre-Diabetes

• FBG 100-125 mg/dl
• 2 hour OGTT

140-199 mg/dl

www.diabetes.org

Prevalence of Glucose Abnormalities (%)

4.9 2.1 18.2 74.8 Known Diagnosis Unknown Diagnosis Prediabet es Normal Glucose Tolerance

Diabetes Prevention Program

• 3200 adults with IFG + IGT
• 3 Groups

Standard care Intensive lifestyle MTF

N Engl J Med. 2002 Feb 7;346(6):393-403.

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Diabetes Prevention Program

• Lifestyle intervention

Goal 7% weight reduction Low-calorie, low fat diet Exercise 150 min/week Intensive education

• F/U 2.8 years

N Engl J Med. 2002 Feb 7;346(6):393-403.

Diabetes Prevention Program

• Metformin should be

considered if Very high risk:

• IGT + IFG

Obese <60 years of age

% of Patients developing Diabetes

11 7.8 4.8 2 4 6 8 10 12 Usual Care Metformin Lifestyle

N Engl J Med. 2002 Feb 7;346(6):393-403.

Weight Loss

• 500-1000 calorie reduction
• Diet alone is generally not effective long-

term

• Exercise is important for weight

maintenance and improved insulin sensitivity

• Structured programs that include

education, diet, exercise, and regular contact can produce sustained weight loss of 5-7%

• ADA. Diabetes Care 31 (Suppl 1):S61-S78

MNT

• Carbohydrates:

The total amount is more important than the type in determining glycemic effect Low glycemic index foods may reduce PPG

• ADA. Diabetes Care 31 (Suppl 1):S61-S78

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MNT

• Protein

15-20% of total calories High-protein, low-carb diets

• Short-term weight loss
• Improved glycemia
• Long-term safety and efficacy is

unknown

• Increased LDL
• ADA. Diabetes Care 31 (Suppl 1):S61-S78

MNT

• Fats

Saturated fats <10% of total calories Monounsaturated fat and CHO should be 60-70% of total calories Cholesterol

• <200 mg/day if LDL >100 mg/dl
• ADA. Diabetes Care 31 (Suppl 1):S61-S78

Efficacy of MNT

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 MNT MNT + DSMT UKPDS Franz Kulkarn i Glasgo

Pastors et al. Diabetes Care 2002;25:608-613

A1C Reduction %

• 4 states do not mandate that

insurers cover diabetes treatment and supplies

Alabama Idaho Ohio North Dakota

Insurance Coverage

Pastors et al. Diabetes Care 2002;25:608-613

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• MNT was associated with a

reduction in

Utilization of hospital

services by 9.5% Utilization of physician services by 23.5%

• Savings exceed costs of MNT in

patients > 55 years

Insurance Coverage

Pastors et al. Diabetes Care 2002;25:608-613

U.S. Adults with Diabetes who have ever attended Diabetes Self-Management Class

www.cdc.org

NHANES Data

36.9 49.4 56.8 10 20 30 40 50 60 70 80 90 100 A1C <7%

1999-2000 2001-2002 2003-2004 Hoerger et al. Diabetes Care 31:81-86, 2008

Measuring Success

ADA1 ACE2 A1C <7%* <6.5% Fasting/preprandial BG 90-130 <110 Postprandial BG <180 (peak) <140 (2 hour)

*Goals should be individualized Risks/Benefits of a “normal” A1c (< 6%) are unclear

• 1. ADA Clinical Practice Recommendations. Diabetes Care 30 (Supp. 1), 2007;
• 2. AACE Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus; Endocr Pract;13(Supp 1), 2007.

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ADA/EASD Consensus Algorithm

Nathan et al. Diabetes Care 2006;29:1963-1972.

Matching Pharmacology to Pathophysiology

Plasma glucose ↓Insulin secretion ↑Hepatic glucose

• utput

↓Peripheral glucose uptake

α-Glucosidase inhibitors Incretins Pramlintide

Metformin (glitazones) Glitazones (metformin) Insulin SFU Glinides Incretins Glucose influx ↑ Glucagon secretion

Incretins Pramlintide

Proportion of Patients Achieving A1C <7.0%

Beta cell function declines over time regardless of therapy

Turner et al. UKPDS 49; JAMA. 1999;281(21):2005-12

5 10 15 20 25 30 35 40 45 50 3 year 6 year 9 year

Diet SFU Metformin Insulin

Greater glycemic durabililty with Metformin and Rosiglitazone Monotherapy

p<0.001 p<0.001

Kahn et al. N Engl J Med. 2006;355:2427-43

5 10 15 20 25 30 35 Rosi Met Gly

Failure rate (%)

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Conclusions

• Diabetes places a substantial clinical and

economic burden on the U.S.

• Lifestyle changes, as part of a multi-

disciplinary approach, can prevent or delay DM

• Initial therapy should be individualized

and goal-directed

Type 2 Diabetes in Children

Dana S. Hardin, M.D.

Associate Professor The Ohio State University Nationwide Children’s Hospital

Incidence

• Causes 2 - 3% of all cases of

diabetes in children

• Mean age of diagnosis 12 - 14

years

• Highest incidence in ethnic groups

with high prevalence of type 2 DM

Definition

• Diabetes mellitus which does NOT

require insulin for survival

• Occurs in someone less than 18 years
• f age.
• Does not meet the criterion for

maturity onset diabetes of youth (MODY)

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Characteristics Associated with Increased Incidence

• f Type 2 DM
• Obesity
• Family history of adult-onset type 2 DM
• Acanthosis nigricans
• Children of mothers with gestational

diabetes

• High-risk ethnicity
• Pima children ages:

5-14 1:1000 15-24 9:1000

• Manitoba Native Indians ages:

7-14 0.5:1000

• Japan:

2.8-44.6:100,000

• Less well studied in other ethnic groups

Incidence by Ethnicity

Incidence in Hispanics and Blacks

• Southern California 21% of diabetic

Hispanic patients (Glasser, J.Invest.Med. 1995)

• African-American children had odds ratio
• f 3.5:1 (boys) and 6.1:1 (girls) compared to

whites (Pinhaus-Hamiel, J.Ped. 1996)

• Houston, TX 12.6% of all DM in children

(Yafi and Hardin JPEM 2004)

Pathophysiology of Type 2 Diabetes is Similar to Adults

• Insulin resistance
• Impaired insulin secretion
• Excessive hepatic glucose production

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Insulin Secretion in Type 2 Diabetes

• Initially insulin secretion is augmented to meet

the demands of impaired insulin action.

• Eventually β-cells become “exhausted” and

glucose intolerance develops.

• First phase insulin response remains intact until

type 2 DM has been on-going for some time.

• Cause of β-cell exhaustion is likely to be glucose

toxicity in a genetically predisposed β-cell.

• Type 2 DM patients have significantly

decreased insulin sensitivity

Demonstrated by fasting hyperinsulinemia Demonstrated by high insulin to glucose ratio post-prandially Confirmed by hyperinsulimic euglycemic clamp studies

Insulin Resistance in Type 2 DM

Insulin-Mediated Whole- Body Glucose Uptake

(DeFronzo, Jm.J.Phys., 1979)

1 2 3 4 5 6 7 8 9 10

Controls NIDDM Glucose Uptake (mg/kg/min)

Increased Hepatic Glucose Production in Type 2 DM

• Increased hepatic glucose production

and hepatic insulin resistance (DeFronzo, Diabetes 1981)

• Increased hepatic glucose production

in MZ twins discordant for type 2 DM (Vaag, J.Clin.Invest., 1995)

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Contribution of Gluconeogenesis and Glycogenolysis

(Consoli, Diabetes, 1989) Hepatic Glucose Output (µmol/kg/min)

5 10 15 20 25 Control NIDDM

Dose-Response Curve Relating Insulin to the Suppression of HGP

Portal Insulin Concentration

Goals of Treatment

• Correct hyperglycemia to prevent

complications. Traditional the focus has been on reducing pre-meal glucose levels. Reduction of post-prandial glucose levels is equally important.

• Minimize the risk of hypoglycemia.
• Promote optimal psychological and social

adaptation to living with diabetes.

Glycemic and A1c Targets

< 7.0 < 7.5 < 8.0 < 8.5 %HbA1c > 80 > 90 > 100 > 100 2-4 AM 80-150 90-160 100-180 100-200 Before bed < 180 < 180 < 200 < 200 2-3 hour postmeal 70-150 70-150 70-150 100-180 Premeal >13 years 7-12 years 3-6 years 0-2 years Blood Glucose mg/dl

Kaufman et al Contemporary Pediatrics 16:112,1999

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Metabolic Consequences

• f Diabetes
• Dehydration

Frequent drinking (polydipsia) Frequent urination (polyuria)

• Weight loss
• Loss of muscle mass

Metabolic Consequences

• f Diabetes
• Type I diabetes – acidosis and death
• Type 2 diabetes – hyperosmolar coma
• Chronic Illness – worsening of

underlying disorder

• Neonatal diabetes – failure to thrive
• Retinopathy
• Nephropathy
• Neuropathy
• Co-Morbidities

Early cardiovascular disease Hypertension Hyperlipidemia

Long-term Complications Resulting from Hyperglycemia

• Retinopathy

pre-pubertal diabetes duration related to retinopathy, 27% of pts (Donague et al, Diabetes Care 20:77,97)

• Nephropathy

Microalbuminuria 9.0%, macro 3.7% macroalbuinuria

(Olsen et al, Diabetic Medicine 16:79,99)

• Neuropathy
• 138 pts >9, duration >2 yrs, nerve conduction velocity, distal

latency and action potential amplitude impaired in adolescent pts (Riihimaa et al, Diabetes Care 24:1087,2001)

• Macrovascular- autopsy data suggestive

Complications Begin Before Puberty

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• Early recognition and treatment

Screening high risk groups (those with at least three risk factors: obese, FH, acanthosis, high risk ethnic group) Random Blood glucose level Fasting blood glucose level OGTT Insulin levels

• Aggressive therapy
• Prevention of diabetes development

Prevention of Diabetes Complications

Screening High Risk Groups – Type 2 Diabetes

• If at least three risk factors:
• bese, FH, acanthosis, high risk

ethnic group

• Random Blood glucose level
• Fasting blood glucose level
• OGTT
• Insulin levels

Acanthosis Nigricans; a Feature of Insulin Resistance Syndrome

AXILLA NECK

Flow Sheet for Acanthosis Nigricans (AN) Referral AN (Use Hale scale to grade) – check posterior neck and axilla

FBG > 126 or HbA1c > 9% ketones moderate or high Refer to Endo for immediate insulin treatment YES

• 1. Body wt > 95%
• 2. BMI > 27

YES Age < 6 > 6 Nutrition counseling Lab studies* Lab studies* Nutrition, Random glucose level (RBG) <126 F/up in 6 months w/ random glucose level >126** check a 2hr OGTT check urine for ketones NO FBG >126 and HbA1c < 9% ketones negative Glucometer, Metformin (250 mg/day po) Refer to Endo for f/up consult Refer to Specialist Abnormal OGTT (fasting glucose >126 &/or 2hr >180) Prepubertal Pubertal (Tanner 2 - 5) Negative ketones and Normal OGTT F/up 6 months NO No Treatment ** If random blood sugar >200 mg/dl, check HbA1c and fasting blood sugar – then follow as below * Lab studies If patient also has short stature consider thyroid function tests &/or Cortisol levels Evaluate for hypertension

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Prevention of Type 2 DM in Children

• Pediatricians need to teach healthy eating

habits and encourage exercise.

• Address overweight patients directly about
• weight. They won’t “grow out of it!”

Adolescence Likely Increases Risk of Obesity

• Early puberty leads to reduced insulin

sensitivity

• Insulin hyper-secretion:

compensation for reduced insulin sensitivity response to increased GH

Adolescence Likely Increases Risk of Obesity

• Sex-dependent changes in insulin

sensitivity (Travers, et al. JCEM 80:172-178,1995)

• Systolic BP changes with

pubertal stage independent

• f age

(Weir, et al. J Adolesc Health Care 9: 465-469, 1988)

• Lipid variability by

pubertal stage

(Belcher, et al. Prev Med 22:143-153,1993)

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Females 6-11 Males 6-11 Percent Percent Males 12-19 Females 12-19

Trends in Child & Adolescent Overweight

Note: Overweight is defined as BMI >= gender- and weight-specific 95th percentile from the 2000 CDC Growth Charts for the United States. Source: National Health Examination Surveys II (ages 6-11) and III (ages 12-17), National Health and Nutrition Examination Surveys I, II, III and 1999-2000, NCHS, CDC.

1963-67 1971-74 1976-80 1988-94 1999-2000 1966-70

5 10 15 20

5 10 15 20

20.6% obese 17% overweight 36.6%

BMI of Ohio BMI of Ohio’ ’s 3 s 3rd

rd Graders

Graders

Boys = girls Poor, rural > urban

Ohio Dept Health, 2006

Environmental causes of Obesity in Children

• Food choices

Fast food

• Increased portion sizes
• Sedentary behavior

Television Video games

• Family environment
• Socioeconomic issues

Summary

• Type 2 diabetes in children is caused by the

same disordered metabolism as in adults.

• Certain patients are at greater risk than
• thers.
• High risk patients should be screened for type

2 diabetes.

• Type 2 diabetes can be prevented, but when

present should be treated aggressively.