DiabetesA Major Health Problem for All

Stuart R. Chipkin, MD, FACESchool of Public Health and Health Sciences

University of Massachusetts, Amherst

Diabetes- Precursors and Complications

I. Diabetes- Major cause of morbidity and mortality in US and Russia

II. Risk factor analysis1. Nutrition- Diet choices2. Physical activity and inactivity3. Other Risk factors- blood pressure, tobacco, cholesterol,

III. Research/program description1. Pre-diabetes: Research study to compare physical activity, medication or combination

- Outcome: insulin sensitivity2. Diabetes: Share diabetes personnel with four primary care sites

- Outcome: laboratory data (a1c) and ER visits3. Risk factors for complications: Electronic Medical Record data collection, state guidelines promotion, case manager utilization

- Blood pressure, cholesterol, foot examinations, eye examinations

Classification of Diabetes Mellitus by Etiology

Type 1 -cell destruction—complete lack of insulin

Type 2 -cell dysfunction and insulin resistance

Gestational -cell dysfunction and insulin resistance during pregnancy

Other specific types • Genetic defects of -cell function• Exocrine pancreatic diseases• Endocrinopathies• Drug- or chemical-induced• Other rare forms

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• Type 1 diabetes– The main abnormality is absolute insulin deficiency

• Type 2 diabetes– Both insulin resistance and relative insulin

deficiency contribute

• Glucotoxicity and lipotoxicity– Poor metabolic control worsens insulin deficiency

and insulin resistance

Defects in Diabetes

• Current estimates:• Over 24 million people in U.S. (7%)• Over age 60, rates exceed 20%

• Recent increases of 20% may be reaching a plateau

• type 1 = 10% (2 million)• type 2 = 90% (21 million)

• Currently 6-7 million are still undiagnosed• Prevalence of “pre-diabetes” over 42 million • Total treatment cost: $174 billion/yr

Diabetes in the U.S.

Diabetes PrevalenceRussian Federation

Year Definition Sex Age Group

Sample Size Prevalence(%)

2001 Questionnaire, self reported diabetic Males 25-64 533 2.3

2001 Questionnaire, self reported diabetic Females 25-64 1135 4.3

Medical Complications of Hyperglycemia

• Microvascular– Eye: retinopathy, cataracts, glaucoma – Renal: kidney failure– Nerve: peripheral neuropathy (sensory, painful), autonomic

neuropathy (cardiac, gastrointestinal, urological)• Macrovascular

– Cardiovascular disorders: Coronary artery disease, heart failure, cardiomyopathy

– Cerebrovascular disorders: stroke– Peripheral vascular disease

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Retinopathy in Diabetes Patients- Northwest Russia (Arkhangelsk )

Dedov I et al; Rev Diabet Stud. 2009 Summer; 6(2): 124–129.

Cataract Prevalence in Diabetes Patients- Northwest Russia

Dedov I et al; Rev Diabet Stud. 2009 Summer; 6(2): 124–129.

Diabetes Patients- Northwest Russia

Dedov I et al; Rev Diabet Stud. 2009 Summer; 6(2): 124–129.

Consequences of Diabetes• Premature morbidity and mortality

– Cardiovascular disease risk increased 2-4 times• Exceeds cost of treating all other complications

combined• Stroke risk increased 2.5 times

– Leading cause of new blindness in people 20-74 years old

– Leading cause of non-traumatic amputation• Reportedly higher rates in Russia

– Leading cause of kidney failure

Key Facts- World Health Organization• Worldwide, more than 220 million people have

diabetes. • In 2005, an estimated 1.1 million people died from

diabetes.• Almost half of diabetes deaths occur in people under

the age of 70 years; 55% of diabetes deaths are in women.

• WHO projects that diabetes deaths will double between 2005 and 2030.

• Healthy diet, regular physical activity, maintaining a normal body weight and avoiding tobacco use can prevent or delay the onset of diabetes.

Measures of Hyperglycemia• Random plasma glucose (RPG)— without regard to time of last meal

• Fasting plasma glucose (FPG)— before breakfast

• Oral glucose tolerance test (OGTT)— 2 hours after a 75-g oral glucose drink

• Postprandial plasma glucose (PPG)— 2 hours after a meal

• Hemoglobin A1c (A1C)— reflects mean glucose over 2–3 months

• Fructosamine/glycated serum protein— reflects mean glucose over 1–2 weeks

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American Diabetes Association. Diabetes Care. 2010; (suppl 1)

*Requires confirmation by repeat testing

Symptoms of diabetes plus random plasma glucose 200 mg/dL (11.1 mM)*

orFasting Plasma Glucose 126 mg/dL (7mM)*

or2-h PG during a 75-g OGTT 200 mg/dL (11.1 mM)*

orA1c > 6.5%

Making the Diagnosis of Diabetes

Glucose Tolerance Categories

American Diabetes Association. Diabetes Care. 2010; (suppl 1)

Fasting Plasma Glucose 2-hr Post Prandial Glucose(OGTT)

126

60

80

100

120

140

160

180

200

Plasma glucose(mg/dL)

Normal

Diabetes Mellitus

240

220

Diabetes Mellitus

Normal

IGT

IFG

Impaired Fasting Glucose and Impaired Glucose Tolerance

Different conditions intermediate Between Normal and Diabetes

Impaired Glucose Tolerance (IGT)

• 2-h PG on OGTT 140 but 200 mg/dL

• Predicts increased risk of diabetes and cardiovascular disease

Impaired Fasting Glucose (IFG)

• FPG 100 but 126 mg/dL• Predicts increased risk

of diabetes and micro- and macrovascular complications

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Who Should Be Tested for Diabetes?Consider if One or More of the Following Apply

• Symptoms suggesting diabetes: weight loss, hunger, urinary frequency, blurred vision

• Age >45 (>30 if patient has other risk factors)• Prior IGT or IFG or family history of diabetes• Prior gestational diabetes or baby weighing >9 lb (4.1kg)• Women with polycystic ovarian syndrome (PCOS)• Obesity (BMI 25 kg/m2), especially adolescents• African, Latino, Asian, or Native American ancestry• History of vascular disease or hypertension

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S11-S14;AACE/ACE medical guidelines. Endocr Pract. 2002;8(suppl 1):40-82

Prerequisites for a Prevention Program• Important health problem posing a significant

health burden on society• Well-understood natural history with identifiable

parameters that measure progression to disease• Test to identify the pre-disease state that is safe,

acceptable and predictive• Safe, effective and reliable means of preventing or

delaying disease • Ability to find high-risk individuals and the cost of

the intervention should be cost-effective and not burdensome

Sherwin R et al; Diabetes Care 27:S48-S54, 2004

Etiology of Type 2 Diabetes Impaired Insulin Secretion and Insulin Resistance

Type 2 diabetes

Genes and environment

Impaired insulin secretion Insulin resistance

Impaired glucose tolerance

Progressive hyperglycemiaand high free fatty acids

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Natural History of Type 2 Diabetes

Macrovascular complicationsMicrovascular complications

Insulin resistance

Impairedglucose tolerance

Undiagnoseddiabetes Known diabetes

Insulin secretion Postprandial glucose

Fasting glucose

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Prevention of Type 2 Diabetes

• Insulin resistance may be an important early stage of intervention

• Evidence exists for interventions to increase insulin sensitivity

Clustering of Factors Reflecting Insulin Resistance in Russia

Sidorenkov et al. BMC Public Health 2010, 10:23

Diabetes Prevention• Case study

45 year old woman comes to see you because her older brother was recently diagnosed with diabetes. She is overweight, tries to avoid sugar, and says that she exercises when she cleans her house. She has been told of high blood pressure and high cholesterol. She was told to exercise and decrease her salt. Her father had diabetes and had a leg amputation.

Diabetes prevention• Case study

Physical examination notes a blood pressure of 150/88, pulse of 76 and BMI of 29 kg/m2.

Fasting laboratory test shows: - Glucose of 122 mg/dl (6.8 mM)- Electrolytes and kidney function normal- Liver tests (ALT/AST are twice normal) - Triglyceride= 280 (3.2 mmol/L)- HDL= 29 (0.75 mmol/L)- LDL= 150 mg/dl (3.9 mmol/L)

Diabetes Prevention• Which of these would you do next?

– Tell her to keep exercising and watching her diet.– Tell her to cut out all sugar in her diet.– Find out more about why she doesn’t exercise

more.– Find out how she defines a healthy diet.– Discuss barriers to physical activity.– Start medication.

• Are there other resources for her?– Family– Work– Community

Diabetes Prevention- Finnish Study

• Incidence of diabetes– Control group: 59 (23%)

• 6% per year– Intervention group: 27 (11%)

• 3% per year– Overall risk reduction of 58% – Diabetes did not develop in any of the subjects

who reached at least four of five goals

Tuomilehto et al; NEJM 344: 1343-50, 2001

Diabetes Prevention Program• Crude incidence (cases per 100 person-years)

- Placebo 11.0- Metformin 7.8- Lifestyle 4.8

- Estimated cumulative incidence of diabetes- Placebo 28.9%- Metformin 21.7%- Lifestyle 14.4%

• Compared with placebo, diabetes risk was – 58% lower in lifestyle group– 31% lower in metformin group

N Engl J Med; 346: 393-403, 2002

Diabetes Prevention Program

• Number needed to treat (three years)• Lifestyle 6.9• Metformin 13.9

• Advantage of lifestyle was greater in• Older subjects• Lower BMI

What about metformin PLUS lifestyle?

Ramachandran A et al; Diabetologia 49: 289-297, 2006

Green= Control

Relative Risk Reduction:- Turquoise= Lifestyle (p=0.018)- Red= Metformin (0.029)- Blue= Metformin + Lifestyle (0.022)

Progress to DMCntrl= 55%

LSM=39.3%MET=40.5%LSM+MET= 39.5%

India Diabetes Prevention Program

• While metformin and lifestyle both prevented or delayed onset of diabetes, there was no additive effect.

• Compared with U.S. DPP, India DPP:– Used smaller dose of metformin– Had baseline diets close to recommended– Subjects did not lose weight

Impact of Energy Deficit on Insulin Sensitivity

Insulin ConcentrationsRest and Steady State (mean of 50, 55, 60')

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

Rest SS Rest SS

Insu

lin (u

U/m

l)

PostPre Pre Post

Pre PrePostPost

NEG BAL

*

Black SE et al: J Appl Physiol, 99:2285-2293, 2005

Research QuestionEnergy Metabolism Laboratory

• Examine the impact of three strategies on insulin sensitivity in people with pre-diabetes (either IFG alone or IFG with IGT)– Metformin alone– Structured, supervised exercise program (3x per

week for 12 weeks)– Metformin + exercise

• Outcome measures– Insulin sensitivity (euglycemic hyperinsulinemic clamp)– Weight, BMI, waist circumference, blood pressure– Fasting glucose, lipid profile, body composition

Impact of metformin, lifestyle or both “Pre-diabetes” subjects

Malin S et al IPE, Miami, FLA 2010;

Diabetes • Case study

51 year old man presents with increasing fatigue and muscle weakness. He does manual work and has noticed a change in his endurance. While he thought he was just getting older, a fellow employee saw him going to urinate several times in one shift and checked his blood sugar using a meter; the glucose was 360 mg/dl (20 mM).

He has not been to the doctor in many years. He smokes 1 pack of cigarettes per day and drinks 1 liter of vodka every 2 days. He plays soccer on weekends “but only in nice weather”. He lives alone.

His mother had diabetes- so did her siblings.

Diabetes- case studyPhysical examination:Pulse= 96 BP=160/98 BMI=36 kg/m2 Fundi: small microaneurysmsNeck: no goiter, no bruitsLungs: clear. Heart: normal heart sounds

(tachycardia)Abdomen: soft, bowel sounds present. No

liver/spleen enlargementExt: no swelling. Pulses in feet present. Skin is

dry and cracked.Neuro: No Achilles reflexes but patellar 2/2

Diabetes- case study• Laboratory tests:

– Glucose= 480 mg/dl (23.3 mmol/L)– Potassium= 3.8 meq/L– Creatinine= 1.9 mg/dl (168 umol/L)– Triglycerides= 480 mg/dl (5.4 mmol/L)– HDL cholesterol= 18 mg/dl (0.47 mmol/L)– LDL cholesterol= 175 mg/dl (4.5 mmol/L)– Urine: no ketones, 3+ glucose

Diabetes- new onset• What are next steps• Education- who does this?

– Diet– Physical activity– Self blood glucose monitoring– Medications

• How can you implement your plan?– Family – Work– Community

Number of people with diabetes 9,624,900Percent with impaired glucose tolerance (20-79 years)

16.7

New cases of type 1 diabetes (children <14 years; new cases per 100,000/year)

12.1

Deaths attributable to diabetes (20-79 years)= 182,103

http://www.diabetesatlas.org/map

Estimates for Diabetes in Russia2010

Survey of Diabetes Awareness• Russia Longitudinal Monitoring Survey (RLMS-

www.cpc.unc.edu/rlms): – 38 sites across Russian Federation (St. Petersburg, Moscow

and 36 districts based on SES, urban/rural status status• Major findings:

– Over half the individuals who reported having diabetes did not receive any formal medical treatment or dietary advice.

– Half those who were “diabetes aware” in this survey were receiving no medical treatment, not even advice about weight loss or diet.

– Limiting factor for medication changed during the study from availability to affordability

Perlman F and McKee Martin Diab Res and Clin Pract 80:305-313, 2008.

Percent of Patients with Diabetes Reaching A1C Goal < 7% in 2010

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100%% HgbA1c 7 and less

JAN FEB MAR APR MAY JUN JUL AUG AVG

Diabetes- Risk Factors for Complications• Case study

67 year old man comes to see you after being seen in hospital for infected foot ulcer. He has had diabetes for 18 years. Also has poorly controlled hypertension and high cholesterol. He is on a diuretic for HTN and a low dose statin for cholesterol. He was told he should take insulin for his diabetes. He went to a diabetes education program 10 years ago.

He does not monitor his blood sugars at home. He “tries” to follow a diet. He does not exercise. He used to smoke more but has decreased. He did not smoke while in the hospital.

His father died from kidney failure due to diabetes. His older brother had a stroke. He lives with his wife; he has two children who are married and live nearby.

Diabetes- Risk Factors for Complications

Physical examination notes a blood pressure of 140/90, pulse of 72 and BMI of 31 kg/m2. He has background retinopathy, clear lungs, systolic heart murmur and benign abdomen. His feet are dry and pulses are poor. He does not feel a monofilament on his toes. There is a healing ulcer on the right foot- 3 cm in diameter over the lateral malleolus.

Laboratory test:- a1c= 11%- Triglyceride= 160 mg/dl (1.81 mmol/L)- HDL= 30 mg/dl (0.77 mmol/L)- LDL= 118 mg/dl (3.1 mmol/L)- creatinine= 1.9 ()- urine albumin:creat ratio= 80

Diabetes- Risk Factors for Complications

• What other questions do you have for him?

• How do you prioritize his problems?• How will you address his problems?

– Immediate vs. Long-term– Other professionals to involve– Community resources

Percent of Patients with Diabetes Reaching LDL Goal < 100 mg/dl (<2.59 mmol/L) in 2010

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JAN FEB MAR APRIL MAY JUNE JULY AUG AVG

UMass School of Public Health & Health SciencesAreas of Diabetes Research

• Prevention– Focus has been on improving insulin sensitivity and

contribution of combining medication with physical activity– Limitations: unclear applicability to clinical endpoint– Challenges: Controlling diet, measuring activity outside of

protocol– Importance: Relatively poor understanding about details of

• Type of exercise: aerobic vs. resistance• Duration or intensity of exercise• Frequency of exercise

• If exercise is a drug, we know relatively little about the dose, frequency, or duration of this “medicine” in terms of preventing diabetes

UMass School of Public Health & Health SciencesAreas of Diabetes Research

• Strategies to maximize diabetes care– Integrate specialized services within an outpatient primary care practice

• Endocrinologist, physician assistant, nurse educator, dietitian• Involve other specialties (podiatry, behavioral health, physical therapy,

ophthalmology, dental, renal)– Educational conferences on difficult cases and relevant topics– Limitations:

• Data from electronic medical record combines all values from all patients (even repeats)

• Applicable to patients participating in health services (but Massachusetts now requires all residents to have insurance)

• Uncertain which components were most effective. – Challenges

• How to evaluate program (Difficult to track visits/admissions to Emergency or Hospital, how quantify “prevented event”)

• Implementing life style changes (diet and exercise– Importance

• Increasing numbers of diabetes patients will utilize increasing health care dollars unless effective strategies identified to maximize care in outpatient setting.

UMass School of Public Health & Health SciencesAreas of Diabetes Research

• Prevention of diabetes-related complications: Focus on risk factors– Utilize electronic medical record (EMR) to track

• Lipid profile• Blood pressure• Urine albumin:creatinine ratio• Foot examinations

– Limitations• Some aspects of EMR difficult to abstract (e.g., foot exams)• Unsure which interventions were most effective

– Challenges• Multiple medicines with side effects• Implementing life style changes (diet and exercise)• Maintaining changes over time course needed to prevent poor outcomes

– Importance• Large cost of diabetes relates to its complications

Clinical Trial:Lots of Support to Optimize Results

• DPP– Meeting with case manager 16 times over first 6 months, and

monthly thereafter– Group courses lasting 4-6 weeks available every 3 months– Two supervised exercise sessions offered every week– Incentives for those not achieving weight loss

• Tapes, equipment, membership, low-calorie foods, eating plans, home visits

• DPP– 50% achieved weight loss goal after six months

• 38% in lifestyle intervention group maintained at least 7% weight loss at the end of the study

– 74% increased physical activity after 24 weeks• 58% met goal at end of study

What Causes High Blood Sugar? (type 2)

Increased glucose release

Decreased glucose uptake

Impaired insulin secretion

Post receptor defects

• https://apps.who.int/infobase/Publicfiles/Estimated%20overweight%20obesity%20males.pps

Undiagnosed diabetes 5.9 million

Prevalence of Glycemic Abnormalities in the United States

Additional 24.6 million with IGT

Diagnosed type 2 diabetes10 million

Diagnosed type 1diabetes ~1.0 million

Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm; Harris MI. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK; 1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001

US Population: 275 Million in 2000

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Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM)

• 5269 subjects (59% female)• Average BMI = 30.9 kg/m2 • Average blood pressure = 136/83 mm Hg

– 43.5% had hypertension• Sedentary- 26.8%• Fasting plasma glucose = 5.8 mM (104

mg/dl)• 2 hour plasma glucose = 8.7 mM (157

mg/dl)