Marie E. McDonnell, MD

Director, Brigham and Women's Diabetes Program

Chief, Diabetes Section

Division of Endocrinology, Diabetes and Hypertension

Brigham and Women’s Hospital

Challenging cases from Diabetes Clinic

Disclosures

• No disclosures

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• T1 and T2 Diabetes

• Monogenic diabetes

• CFRD (Boston Children’s Hospital)

• Cancer-related diabetes (Dana Farber Cancer Institute)

• Post-pancreatectomy diabetes

• Diabetes in Pregnancy (BWH Maternal Fetal Medicine)

• Syndromic diabetes

• Secondary diabetes 3

Cases

1. High triglycerides – sheep in wolf’s clothing or just a

wolf?

2. Complex Insulin therapy– pulling back the curtains with Continuous Glucose Monitoring

3. Diabetes in pregnancy – when the pattern doesn’t fit

4. Recurrent hospitalization for DKA – what are we missing?

5. A tropical cause of Pancreatic diabetes – turning bad luck into a cure

Diabetic dyslipidemia in clinic

High triglycerides

Low HDL

Small dense LDL

TG: Case 1a 52 year old man with type 2 diabetes (A1c 6.8%) with CAD s/p CABG, hepatic steatosis, hypertension and hyperlipidemia. BMI 26

Medications ASA 81 mg daily Clopidogrel 75mg daily Atorvastatin 40mg daily Carvedilol 3.125mg BID Lisinopril 10mg daily Metformin 1g BID Novolog mix 70/30 –35 units BID

LIPID PANEL

• Non-smoker, no ETOH

• FHx: Father had MI at age 43

Insulin resistance

↓degradation of apo B100

↑hepatic VLDL ↑gut-derived chylomicrons

↑Circulating fatty acids

↑Triglyceride Rich Lipoproteins or TRLs

Lorenzo et al. Impaired Fasting Glucose and Impaired Glucose Tolerance Have Distinct Lipoprotein and Apolipoprotein Changes: The Insulin Resistance Atherosclerosis Study. JCEM 2013

TRL = Triglyceride-rich lipoproteins Watts et al. Demystifying the management of hypertriglyceridaemia. Nature Review Cardiology 2013

How do we define hypertriglyceridemia?

NCEP ATP III = National Cholesterol Education Program NLA = National Lipid Association AACE = American Association of Clinical Endocrinologists TES = The Endocrine Society

To Treat or not to Treat? Triglyceride Controversy

1987

2010

1999

2005

Helsinki Heart Study

VA HIT

FIELD study

ACCORD Lipid

ACCORD Lipid - 2010

• 5518 patients, Age 62, 31% female

• Median follow-up 4.7 years

• 37% previous cardiovascular event

• 60% statin use

• Randomized to fenofibrate + simva OR placebo + simva

Question: Among adults with type 2 diabetes on statin monotherapy, does adding a fibrate reduce risk of cardiovascular disease? - ONLY FIBRATE STUDY ON BACKBONE OF STATIN THERAPY

HDL level = 38 Triglycerides = 162 LDL = 100

By end of study: HDL increased by ~7% TG decreased by 34%/11% LDL decreased by ~24%

Post-hoc analysis of FIELD • Highest therapeutic benefit of Fenofibrate Seen in

patients with elevated TG and Low HDL

Scott et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes care 2009

TG>200 HDL <40

Glycemia has major impact on TG

Karelis et al. Relationship between insulin sensitivity and the triglyceride-HDL-C ratio in overweight and obese post-menopausal women: a MONET study. Appl. Physiol. Nutr. Metab, 2007

TG-HDL ratios

Question 1

Which of the following is not a known cause of secondary hypertriglyceridemia ?

A. Hypothyroidism

B. Nephrotic syndrome

C. Furosemide treatment

D. Adrenal insufficiency

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Question 1

Which of the following is not a known cause of secondary hypertriglyceridemia ?

A. Hypothyroidism

B. Nephrotic syndrome

C. Furosemide treatment

D. Adrenal insufficiency

17

TG: Case 1b

• 63 year old female with obesity (BMI 35), depression, hypothyroidism and type 2 diabetes with non-adherence to medications. A1c 8.3%, TSH 14

DIABETES CLINIC

LIPID PANEL Medications ASA 81 mg daily Zoloft 25mg daily Levothyroxine 100mcg/d Metformin 500mg BID Glipizide 5mg BID

TG: Case 1b

• 63 year old female with obesity (BMI 35), depression, hypothyroidism and type 2 diabetes with non-adherence to medications. A1c 8.3%, TSH 14

DIABETES CLINIC

LIPID PANEL Medications ASA 81 mg daily Zoloft 25mg daily Levothyroxine 100mcg/d Metformin 500mg BID Glipizide 5mg BID

Optimize thyroid status and diabetes control

What do the guidelines say about TG? AACE

Endo society

NCEP ATP III NLA ACC

Treat if >500 Treat if >500 Treat if >500 Treat if >500 Treat if >500

Consider fibrates to

improve ASCVD outcomes when TG

concentrations are ≥200 and

HDL <40

Consider treating with fibrates if high TG and low HDL despite statin-lowering therapy

Non-HDL (LDL + VLDL) as target

<130 - CHD <160 – multiple RF <190 – 1-2 RF

If non-HDL above goal & TG 200-499 after LDL goal is reached, consider adding fibrate

When TG 200 and 499 mg/dL, the targets of therapy are non–HDL-C and LDL-C

Focus on optimizing statin therapy

AACE = American Association of Clinical Endocrinologists NLA = National Lipid Association ACC = American College of Cardiology NCEP = National Cholesterol Education Program

RF = risk factors CHD = Coronary heart disease ASCVD = Atherosclerotic Cardiovascular Disease

Options for triglyceride lowering

• Fibrates – fenofibrate, gemfibrozil ↓ 30-50%

• Omega fatty acids – 3-4g/d EPA+DHA ↓20-40%

• Niacin – 0.5-2g/d ↓10-30%

• Metformin ↓10-15%

• Pioglitazone ↓10-25%

Future directions

• Pemafibrate trial in type 2 diabetes almost completed (PROMINENT)

• Omega fatty acid trials ongoing

• Dual PPAR alpha/gamma agonists – aleglitazar, saroglitazar

• ApoCIII inhibitors

• (ApoCIII increases VLDL production and prevents clearance of TRLs)

G6 transmitter and receiver Fingerstick calibration required? NO

The Freestyle Libre Flash – Approved in Europe 2016, and 9/2017 in the US for personal use Fingerstick calibration required? NO

Continuous glucose monitoring

24yo man with type 1

diabetes for 12 years

--Omnipod insulin pump x 8

years

--70kg

--Basal 1.1 u/ hour all day

(26u basal, 14u bolus)

--Correction factor: 15; Insulin

to carbohydrate ratio: 1:8

--A1c 7.4%

- Monitors glucose only twice

daily, reports hypoglycemia

overnight

CGM case 2a: Behind the A1c

ETOH

Forgot to Change Pod

Left PDM at Home

ETOH

Home insulin dosing: reliable?

72 yo woman with type 2 diabetes, mild early dementia, 82kg

Elective surgery planned for hip replacement in 1 month

Home regimen: Lantus 120 units, Humalog 15 with meals, Metformin

Long discussion

with patient and

son.

Lantus redosed

by weight: 0.4

units/kg/day = 32

units. Titrated

over one month

to 50 units at

night

Humalog 15 with

breakfast and

dinner only

Metformin

Case 3: Diabetes in Pregnancy, atypical

pattern

• 33yo woman of Scandinavian descent with history of Type 1 DM seen for management during pregnancy.

• PMH: T1Dm diagnosis was made a year after a trial of

Oral agents (metformin and saxagliptin) after which she transitioned to insulin and then an insulin pump. She recalls being told her C-peptide was and that she had Type 1DM.

• FH: father with prediabetes on a military physical completed at age 18; Developed diabetes and has been taking insulin since age 32

28

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During pregnancy she had

an unusual glucotype:

At 28 weeks she had very

low basal insulin needs (<0.2

units/kg/day), high nutritional

needs, total 40 units. Fasting

hypoglycemia, resolved by

suspending basal insulin

overnight

Question 2

For women with insulin-requiring diabetes during pregnancy, insulin requirement increases most dramatically during which weeks? A. 6 to 10 weeks

B. 12 to 16 weeks

C. 22 to 26 weeks

D. 34 to 38 weeks 30

Question 2

For women with insulin-requiring diabetes during pregnancy, insulin requirement increases most dramatically during which weeks? A. 6 to 10 weeks

B. 12 to 16 weeks

C. 22 to 26 weeks

D. 34 to 38 weeks 31

32

• Human Placental

Lactogen

• Cortisol

• TNF alpha

glucose

MODY genes encode nuclear

transcription factors that impact

islet development and insulin

receptor function and insulin

secretory function

Currently 14 are known; 6 most

prevalent

Autosomal dominant

inheritance and variable

penetrance

5% of all diabetes; often

misdiagnosed 33 Fajans, Bell, Polonsky. NEJM, 2001

MODY in South India ?

• 289 patient sample enriched with 152 patients who had already met clinical criteria for MODY (e.g. diagnosis prior to 35 and no Type 1 antibodies)

• 12- gene panel plus exome sequencing to identify putative MODY relevant

variants in genes previously not implicated in MODY.

• MODY 3 (HNF1A) was identified in 7.2%; MODY 12 (ABCC8) was identified in 3.3%. They together accounted for ~ 11% of the cases.

• HNF1A and ABCC8 to be the most frequently mutated MODY genes in South India. Both of these are best treated with sulfonylurea therapy. Both are also associated with transient neonatal hypoglycemia

34 V Mohan, et al. BMC Medical Genetics. 13 February 2018

Further history

• Hypoglycemia history:

–She developed hypoglycemia around ages 12-14, which required regular Juice and snack intake at school to prevent daily symptoms, and improved in high school with dietary changes.

• Post Partum:

–Baby was 9-10lbs upon birth despite overall mean glucose <105 on pump

and CGM.

–Her daughter had severe hypoglycemia at birth which required ICU for 4 weeks.

–Daughter required tube feeding early on, had low O2 sats (93-95%) while sleeping, failed fasting trial at hour 4.

–Passed second trial of fasting (though barely above threshold) prior to d/c from NICU at 28 days

Mom’s Genetic Testing results = “MODY Plus”

• Mutation #1 in the HNF1A gene at c.326+1G>T = “MODY3” – HNF1a monogenic diabetes is characterized by progressive insulin deficiency with a

classical “glucotype” of more nutritional insulin needs than basal needs. It can be usually treated with low dose (often very low dose) sulfonylurea for decades.

AND • Mutation #2: SLC2A2 VUS: predicted to have splicing effects. In its

autosomal recessive form, this can cause Fanconi-Bickel syndrome.

– Fanconi-Bickel is a GLUT2 defect that inhibits transport of both glucose and galactose (causing diabetes) in the liver. This disorder is also characterized by hepatorenal glycogen accumulation and “trapping” (causes hypoglycemia, similar to glycogen storage disease)

We are still waiting on Baby’s genetic testing results.

• 34 yo Jamaican woman with poorly controlled (A1c 10-13%), labile type 1 DM (GAD 65+) diagnosed in her early 20s. Sister also has type 1 diabetes.

• Retinopathy and neuropathy

• Depression, poor social support, mother of 2, Intellectual disability with low IQ

• Multiple admissions for “dehydration” with severe hypomagnesemia and hyperglycemia.

• Presents with nausea, vomiting, diarrhea and poor PO intake for several days. Similar admissions 8 times last 12 months.

• Found to have glucose 302 mg/dl and anion gap of 32, venous pH 7.3, + ketones. Magnesium <1. Admitted for ketoacidosis

Case 4: Recurrent DKA in a young woman with intellectual disability

• Reports taking degludec insulin 4 U qAM and not missing any doses (recently increased from 3 U qAM and having more hypoglycemia), not taking aspart as not eating. Total daily insulin dosage is about 9 units; she is 65kg.

• In previous admissions, has had unusual pattern of: • Rapid resolution of DKA

• Requirement of very little to no insulin for several days (sometimes even requiring dextrose in IVF)

• Then improved appetite, hyperglycemia, requirement of 3-4x home doses of insulin

Case 4: Recurrent DKA in a young woman with intellectual disability

Glucose Trend

HD #1 HD #2 HD #3

43

IV fluid: Magnesium, Saline, Dextrose added HD #2

Basal Insulin held

Differential Diagnosis? • Self-administration of insulin or prolonged action of subcutaneous

insulin?

• Atypical diabetes with Endogenous insulin production?

• Cause of fluctuating insulin resistance? • Insulin receptor antibodies? – not the usual phenotype

• Adrenal insufficiency – recent AM cortisol >20

• Hepatic or renal failure – not present

A Look Back at Prior Labs Ref.

Range

12/29/14 10:43

4/15/15 13:06

4/21/15 20:29

4/22/15 09:42

10/18/17 21:41

12/20/17 20:45

2/27/18 18:21

2/28/18 20:42

Insulin 2.6 - 24.9 uIU/mL

5.1 <0.5 (*)

2.9 1.3 (L)

C-Peptide

1.1 - 4.4 ng/mL

0.3 0.1 0.2 (L) 0.4 (L) 0.2 (L)

Pro-insulin

3.6 - 22 pmol/L

8.1 4.3 1.3 (L)

Glucose 276 at 8:26; 372 at 11:33

107 20:14 >500

351 428 191 at 20:53

302 (serum)

219 at 21:00

Armstrong MJ, Gaunt P, Aithal GP et al. Lancet. 2016;387(10019):679-90.

Question 3

What percent of patients with classical type 1 diabetes have a positive stimulated c-peptide indicating persistent endogenous insulin production 10 years after diagnosis? A. 25%

B. 50%

C. 1-2%

D. 8-10%

42 The DCCT Research Group. J Clin Endocrinol Metab. 1987;65:30–36. doi: 10.1210/jcem-65-1-30.

Leighton E, Sainsbury CAR, Jones GC. Diabetes Ther. 2017; 8(3): 475-487

Question 3

What percent of patients with classical type 1 diabetes have a positive stimulated c-peptide indicating persistent endogenous insulin production 10 years after diagnosis? A. 25%

B. 50%

C. 1-2%

D. 8-10%

43 The DCCT Research Group. J Clin Endocrinol Metab. 1987;65:30–36. doi: 10.1210/jcem-65-1-30.

Leighton E, Sainsbury CAR, Jones GC. Diabetes Ther. 2017; 8(3): 475-487

Further Course • HD #4-5, after IVF stopped, she became markedly hyperglycemic, difficult

to control

HD #1 HD #2 HD #3 HD #5 HD #4

Fluids stopped

Diagnosis: MODY 5 with 17q12 recurrent deletion syndrome

• MODY5: mutations of the hepatocyte nuclear factor (HNF)-1 beta gene; pancreatic atrophy

• Progressive beta cell dysfunction and insulin requiring diabetes • Insulin needs typically low but not zero

• Renal abnormalities : magnesium wasting [often predominant]. • This likely causes impaired insulin action

• Developmental delay with intellectual disability • 70% mutations occur de novo, inherited in autosomal dominant

manner

Ardon O, Procter M, Tvrdik T, Longo N, Mao R. Mol Genet Metab Rep. 2014; 1: 71-84

Case 5: Unusual case of Pancreatic diabetes (“Type 3c”)

• 57 year old gentleman with a history of Dengue fever contracted in

Delhi during travels in 2006

• He was hospitalized with severe Dengue complicated by acute

pancreatitis

• He had recurrent episodes of pancreatitis and developed chronic

pain

• Required basal insulin therapy in 2013

• Finally underwent partial pancreatectomy with successful pain

relief in 2015.

Acute Pancreatitis: A rare complication of Dengue fever

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• Mosquito-borne Viral infection

endemic in tropical and subtropical

continents that usually causes Flu-like

illness

• Severe dengue (dengue hemorrhagic

fever-DHF and dengue shock

syndrome-DSS) is a potentially deadly

complication due to plasma leaking,

fluid accumulation, respiratory distress,

severe bleeding, or organ impairment.

• Pancreatitis has been described but is

extremely rare

• The number of cases reported

increased from 2.2 million in 2010 to

3.2 million in 2015

Aedes aegypti

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Pancreatic or “Type 3c” diabetes

49

• Post- Pancreatectomy patient required basal/bolus insulin

therapy. Hypoglycemia was common and became problematic. He eventually decided to move to insulin pump therapy.

• A1c 6.5% on insulin pump, highly regimented patient

• Still struggles with hypoglycemia despite using personal CGM and good prevention strategies.

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Case 5: Unusual case of Pancreatic diabetes (“Type 3c”)

Confidential

Boston Autologous Islet Replacement Therapy

Program (BAIRT)

• Diabetes is a heterogenous condition

• It is up to us to use our skills to identify subtypes in order to direct patients to the best therapies

• Diabetes is INTERESTING and EXCITING field of study so SPREAD THE WORD…

WE NEED MORE OF US!

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Conclusions

Thank you for your care of patients with

diabetes!