AAIM DIABETES WORKSHOP 2015 TRIENNIALRichard Braun, MD

John Kirkpatrick, MD

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Topics for Discussion

• Type 1 Diabetes

• Type 2 Diabetes

• Children & adolescents

• Adults

• PreDiabetes

• Gestational Diabetes

• Morbidity & Mortality Considerations

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Diabetes in the US

National Diabetes Statistics Report, 2014http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf

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Diabetes Prevalence

JAMA. 2015;314(10):1021-1029. doi:10.1001/jama.2015.10029

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Diabetes - Pathogenesis

• Type 1 Diabetes (5-10% in US, Canada, Europe)

• 1A (85%) Insulin deficiency, caused by T-cell immune destruction of pancreatic beta cells – presence of pancreatic autoantibodies*

• 1B (15%) (idiopathic) non-autoimmune islet cell destruction & insulin deficiency

• Type 2 Diabetes (over 90% of cases in US, Canada, Europe)

• Hyperglycemia & insulin resistance with relative reduction of insulin secretion – usually lost ~ 80% of beta cell function by the time of diagnosis (Suggested by high fasting Insulin & C-peptides levels)

• Latent autoimmune diabetes in adults (LADA)

• Spectrum between Type 1 and type 2, sharing genetic features of both. Variable amounts of islet cell antibodies (ICA) and antibodies to glutamic acid decarboxylase (GAD) 65. Display quicker progression to insulin dependence.

*Auto Antibodies – ICA, GAD 65, tyrosine phosphotases, insulinoma-associated protein (IA-2) & IA-2 beta, and zinc transporter (ZnT8)

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Diabetes - Pathogenesis• Monogenic Diabetes formerly Maturity Onset Diabetes of the Young

(MODY) – Accounts for 2-5% DM

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MODY Types – Monogenic defects, Autosomal Dominant

Type Genetic defect Frequency Beta cell defectRisk of

microvascular disease

Optimal treatment

1

Hepatocyte nuclear

factor-4-alpha (HNF4A)

<10 percent

Reduced insulin

secretory response to glucose

Yes Sulfonylureas

2Glucokinase gene (GCK)

15 to 31 percent

Defective glucokinase

molecule (glucose sensor), increased plasma levels of glucose are necessary to elicit normal levels of insulin secretion

Generally no Diet

3Hepatocyte nuclear factor-1-alpha (HNF1A)

52 to 65 percentAbnormal insulin secretion, low renal threshold for glucose

Yes Sulfonylureas

4Insulin promoter factor 1 (IPF1)

Rare

Reduced binding to the insulin gene promoter, reduced activation of insulin gene in response to hyperglycemia

Yes

5Hepatocyte nuclear factor-1-beta (HNF1B)

Rare Yes Insulin

6Neurogenic differentiation factor-1 (NEUROD1 or BETA2)

RarePancreatic development

Yes Insulin

(modified)

Easy to confuse MODY with T2DM in the youngImportance is no insulin resistance (treatment), and family monitoring

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Case

A 25 year-old woman applies for insurance. She was diagnosed with Type 1 Diabetes (T1DM) at age 9. She has had an insulin pump for about 12 years. She monitors her blood sugar 3 to 4 times daily and adjusts the pump dosing accordingly. She reports one or two hypoglycemic episodes per year. She is 5’7” tall and weighs 142 lbs. She has 2 children and is employed as a paralegal. She exercises regularly and has no other medical issues. Current Labs show an A1c of 7.2%, the urine is negative for albumin.

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T1DM - Epidemiology

When individuals move, they assume the higher risk of the new location.Finland and Sardinia have 400 X the risk of Venezuela and parts of China.

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T1DM – Epidemiology (US)• 75% occurs in children, 25 % in adults

• Bimodal incidence peaks, age 4-6 and 10-14; M:F – 3:2

• Incidence & prevalence increasing

JAMA. 2014;311(17):1778-1786.

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Lifetime Risk of T1DM- Family Hx

Affected relative Lifetime risk

Mother 1-4%

Father 3-8%

Both Parents ~30%

Sibling (non-twin) 3-6%

Dizygotic (Fraternal)

twin

8%

Monozygotic (Identical)

twin

30% w/in 10 yrs, 65% by

age 60

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Diagnosis T1DM

• Three presentations predominate

• Polyuria, polydipsia, weight loss

• Diabetic Ketoacidosis, add vomiting, lethargy (30%)

• Silent – being closely monitored

• Diagnostic Criteria

• Fasting Plasma Glucose > 125 mg/dl (7mmol/L)

• Random venous plasma glucose > 200 mg/dl (11.1 mmol/L)

• Oral glucose tolerance test (OGTT) – 2 hours after a 1.75 mg/kg (max 75g) glucose load – plasma glucose > 200 mg/dl (11.1 mmol/L)

• Glycated hemoglobin (A1C) > 6.5 percent

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Treatment T1DMInsulinBalance of tight control And risk of hypoglycemic reactions- Adults A1C < 7 percent (53 mmol/mol)- Children < 7.5 % (59 mmol/mol)

A1C were > 7.5% in >70% of adolescents

Multiple Daily InjectionsInsulin PumpSensor augmented pump therapy

Artificial Beta cell - published on September 17, 2015, at NEJM.org- type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower A1C

level. (- .3 to .5)

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T1DM and Life Expectancy

Men Women

Age Difference in

LE-Population

Percent of

2008 VBT

Difference in

LE-Population

Percent of

2008 VBT

20-24 11.1 yrs 300% 12.9 yrs ~350%

40-44 9.2 300% 10.8 ~350%

60-64 5.6 ~225% 7.1 ~300%

JAMA. 2015;313(1):37-44.

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Copyright © 2015 American Medical Association. All rights reserved.

From: Association Between 7 Years of Intensive Treatment of Type 1 Diabetes and Long-term Mortality

JAMA. 2015;313(1):45-53.

doi:10.1001/jama.2014.16107

Cumulative Incidence of Mortality in the Diabetes Control and Complications TrialData are reported from the Diabetes Control and Complications Trial (DCCT; 1983-1993) and the subsequent observational follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994 to December 31, 2012). Hazard ratios (HRs), CIs, and P values were obtained from a Cox proportional hazards model.

For men vs women, HR = 1.61 (95% CI, 1.09-2.39); P = .02; for the intensive vs conventional treatment groups (intent-to-treat analysis), HR = 0.67 (95% CI, 0.46-0.99); P = .045.

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Association Between 7 Years of Intensive Treatment of Type 1 Diabetes and Long-term Mortality

JAMA. 2015;313(1):45-53.

doi:10.1001/jama.2014.16107

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Copyright © 2015 American Medical Association. All rights reserved.

From: Association Between 7 Years of Intensive Treatment of Type 1 Diabetes and Long-term Mortality

JAMA. 2015;313(1):45-53. doi:10.1001/jama.2014.16107

Table - Separate Models of the Association of Each Time-Dependent Covariate With the Risk of Death and the Corresponding Death Rate Within Categories of Each Covariate

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T1DM Mortality, Alleghany County, PA – 1965-79, Mean age onset 10.8 + 4.2

Diabetes Care 24:823–827, 2001

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Pittsburgh Epidemiology of Diabetes Complications (EDC)Mean age at onset T1DM - 8.3

Life expectancy

At age 10 in 1965-80 – 58.8

Years;

Compared to

44.6 in 1950-64

Diabetes 61:2987–2992, 2012

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Swedish experience survival after CABG with T1DM & T2DM

CABG at 58.8 years in T1DM

67.4 in T2DM

67.5 in non-DM

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Case

• A 22 year-old male, non-smoker applies for life insurance. He is 6’1” tall and weighs 315 lbs, and has a BMI of 41.6. He passed out at a football practice in high school and was found to be dehydrated with glycosuria. Subsequent testing revealed an A1c of 7.1%. Family history was that his mother has hypertension and diabetes. He was diagnosed with Type 2 Diabetes (T2DM). He was started on Metformin at that time and A1c has ranged from 7.1% to 7.9%. The remainder of his laboratory tests are WNL. Efforts at weight loss have been unsuccessful, and he currently plays football at a Division II college.

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T2DM in children and adolescents

JAMA. 2014;311(8):806-814.

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T2DM in children and adolescents

National Diabetes Statistics Report, 2014http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf

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Mean BMI of Adults diagnosed with T2DM

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T2DM in children and adolescents

Arch Pediatr Adolesc Med. 2008;162(7):682-687

- Lag time between obesity and T2DM ~ 10 years in PIMA Indians- Severity of Obesity related to onset of T2DM

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Pediatric Diabetes Consortium• Characteristics of initial 503 patients with T2D

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TODAY Study Group T2D

J Clin Endocrinol Metab 96: 159 –167, 2011

N Engl J Med 2012;366:2247-56.

65% Female, Mean Age 14,73% Hispanic or black

33.8% had HBP at avg F/U 3.9 yrs

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Youth T2D• Not much data for long term study available

• Study in Pima Indians 1965-2002• T2D age onset < 20 or > 20

• Between ages 25 – 55 the age & sex adjusted rate of death from natural causes for youth onset disease was 15.4 per 1000 person-years, versus 7.3 deaths per 100 for older onset.

• Compared with non-diabetics the death rate for youth onset T2D was 3 times as high, and for older onset was 1.4 times as high.

• “The longer duration of diabetes largely accounts for these outcomes.”

JAMA. 2006;296:421-426

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Intensive Control in T2DM

BMJ 2011;343:d4169 doi: 10.1136/bmj.d4169

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BMJ 2011;343:d4169 doi: 10.1136/bmj.d4169

T2DM Intensive control

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Kidney Disease measures & mortality with and without diabetes

Lancet. 2012 November 10; 380(9854): 1662–1673. doi:10.1016/S0140-6736(12)61350-6.

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Case: T2DM

• 48 year old male• Dx: 8 months ago with T2DM

• Non smoker

• PMHx: HTN x 15 years

• FHx: Father MI at 54 (was a smoker)

• MEDS: Metformin 1000mg/d

• Lisinopril/HTCZ 20/25 qd

• PE: BMI 35

• BP 144/94

• Lipids • T Chol 280 mg/dL (15.6 mmol/L)

• HDL 40 mg/dL (2.2 mmol/L)

• Triglycerides 390 mg/dL (21.6 mmol/L)

• LDL not reported

• Fasting GLU 118 mg/dL (6.6 mmol/L)

• HgA1c 6.9%

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The Emerging Risk Factors Collaboration. N EnglJ Med 2011;364:829-841.

Diabetes and Survival, According to Sex and Diabetes Status.

T2DM impact on life expectancy

Emerging Risk Factor Collaboration: T2DM without known vascular disease

The Emerging Risk Factors Collaboration. N Engl J Med 2011;364:829-841

6.3

6.8

5.8

6.4

4.5

5.4

0 2 4 6 8

40 yr Male

40 yr. Female

50 yr. Male

50 yr. Female

60 yr. Male

60 yr.Female

Years of Life Lost

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Risk of Death: DM vs. non DM

• Death Hazard Ratio: DM vs. non

• All cause 1.80

• Renal Dz 3.02

• Coronary 2.31

• Liver 2.28

• Cancer 1.25

Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific DeathThe Emerging Risk Factors Collaboration N Engl J Med 2011;364:829-41.

• “In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors.”

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T2DM : treated HTN

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T2DM: add Albuminuria

• In the last year• 70 mg/g alb/creat

• (7.91 mg/mmol)

• 125 mg/g alb/creat• (14.13 mg/mmol)

• Our UA• 275 mg/g alb/creat

• (31.1 mg/mmol)

• Definitions• NORMAL

• ≤ 30 mg/g creat

• (3.4 mg/mmol creat)

• Microalbuminuria• 30-300 mg/g creat

• (3.4-34 mg/mmol)

• Macroalbuminuria• >300 mg/g

• (34 mg/mmol creat)

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Renal Outcomes in T2DM

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Role of Intensive Glucose Control in Development of Renal End Points in Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis

Arch Intern Med. 2012 May 28;172(10):761-9

Kaplan-Meier plots of proportion of patients with microalbuminuria, macroalbuminuria, reduced creatinine clearance (CrCl), doubling of plasma creatinine, or any one of these, after

diagnosis of diabetes.

UKPDSRetnakaran R et al. Diabetes 2006;55:1832-1839

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Impact of Nephropathy on Risk of Death41

UKPDS 64. Kidney International 2003; 63: 225-232

No nephropathy

Microalbuminuria

⇓⇓⇓⇓ 2.0%

Macroalbuminuria

⇓⇓⇓⇓ 2.8%

ESRD

⇓⇓⇓⇓ 2.3%

1%

3%

5%

19%

DEATH

Annual Risk

Risk of Death: DM vs. non DM• Death Hazard Ratio: DM vs. non

• All cause 1.80

• Renal Dz 3.02

• Coronary 2.31

• Liver 2.28

• Cancer 1.25

Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific DeathThe Emerging Risk Factors Collaboration N Engl J Med 2011;364:829-41.

• “In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors.”

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Type 2 DiabetesWhat if: add Peripheral Neuropathy?

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UKPDS

• At T2DM diagnosis

– 36% men

– 21% women

Had evidence of neuropathy

• At 12 years

– Of those free of any neuropathic abnormality

• 64% men

• 44% women

Developed at least one neuropathy endpoint

(vibratory sensory threshold, ankle jerk reflex, ED in males)

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Multifactorial intervention and

CVD in patients with type 2 DMThe Steno-2 Study.P Gaede et al. N Engl J Med 348:

383, 2003

Peripheral Neuropathy

Vibratory sensory threshold

Ankle jerk reflexED in males

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Diabetic Peripheral Neuropathy

Making the Diagnosis

Questionnaire

Michigan Neuropathy Screening Instrument

EMG

Neurothesiometer

32%

49%

79%

International Journal of Endocrinology. 2013

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JAMA. 2015;314(10):1052-1062. doi:10.1001/jama.2015.9536

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Pre-Diabetes

• 59 year old male $10 million policy

• BMI 26

• BP 120/82

• T Cholesterol 180 (10 mmol/L)

• GLU 94

• HgA1c 5.7%

• Exercises daily

• PMHx: two fasting GLU >100 (5.6 mmol/L)

• Without comment/follow up.

• No tobacco

• 13.5 METS on ETT

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American Diabetes Associationwww.diabetes.org

Pre-Diabetes Definition

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Diabetes Care. 2011 Mar; 34(3): 610–615.

Risk of T2DM by HgA1c

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PLOS ONE | DOI:10.1371/journal.pone.0122698 April 8, 2015

Incidence of Type 2 Diabetes in Pre-DiabeticJapanese Individuals Categorized by HbA1c

Levels: A Historical Cohort Study

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Hemaglobin A1c cut‐‐‐‐off point to identify a high risk group of future diabetes: Omiya MA Cohort Study

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Diabetic Medicine 2012 Jul;29(7):905-910.

Gestational Diabetes

• 36 year old female

• Hx of Gestational Diabetes

• NSVD X 5, last one 8 months ago

• Rx: "shots” each pregnancy

• PE: BP 118/76

• BMI 38

• Ginger 1 gm TID

• Script check: negative

• Cotinine negative by oral fluid

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Gestational Diabetes: Definitions

OVERT DIABETES GESTATIONALDIABETES

• FPG ≥ 126 mg/dL(7.0 mmol/L)

• A1C ≥ 6.5 %

• Random GLU ≥ 200

• (11.1 mmol/L)

� FPG ≥ 92 (5.1 mmol/L)

� At 24-28 weeks

� 75 gm 2 hour GTT

� At least one of the following:

FPG: ≥ 92 mg/dL (5.1 mmol/L) but

≤ 126 mg/dl (7.0 mmol/L)

1 HOUR: ≥ 180 mg/dL (10.0 mmol/L)

2 HOUR: ≥ 153 mg/dL (8.5 mmol/L)

2010 International Association of Diabetes and Pregnancy Study Group2011 American Diabetes Association

Gestational Diabetes

• 10% either T2DM or Latent Type 1

• 1/3-2/3 GDM in subsequent pregnancy

• 20% IGT post partum

• Risk of T2DM

• 20-60%in next 10 years

• 50-75% if BMI > 30

• RR 4.69 at 5 yrs.

• RR 9.34 > 5 yrs.

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www.cdc.gov/diabetes