Islet Function and the Treatment of Diabetes

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diabetes.ucsf.edu a history of innova-on…a vision of a cure

Islet Function and the

Treatment of Diabetes

Gregory Ku, MD PhD Assistant Professor in Residence

UCSF Diabetes Center Division of Endocrinology and Metabolism


Outline

•  The pancreatic beta cell is the key player in all forms of diabetes mellitus. –  Type 1 –  MODY –  Mitochondrial diabetes –  Type 2

•  Can we can prevent beta cell failure in type 2 diabetes?

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The pancreatic islet


Blue = DNA Green = insulin (beta cell) Red = glucagon (alpha cell) Not shown: somatostatin (delta) pancreatic polypeptide (gamma) ghrelin (episilon)

The pancreatic islet and the beta cell

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Type 1 diabetes: autoimmune beta cell destruction

glucagon anti-CD3

Itoh et al., JCI 1993; 92:2313.

Pancreas biopsies from new type 1 diagnoses


Beta cell dysfunction precedes type 1 diagnosis by many years

Koskinen et al. Eur J Endo 2016; 174(3):251-259

Finnish, at risk HLA, screened at 3 months Black line = transient ICA positive, no type 1

n=192 Dotted line = eventual type 1, n=220

p=0.001, 4-6 years no change in HOMA-IR

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Atypical type 1?

•  The patient was a 31-year-old Caucasian female who had been diagnosed with T1D at the age of 5 and treated with insulin thereafter. Her T1D was complicated by retinopathy and nephropathy, and she developed end-stage renal disease in her 20s. During the evaluation, her C-peptide level was found to be 7.32 ng/mL (normal range, 0.8–3.9). Her family history was significant for T1D in her brother and mother, as well as multiple members on the maternal side of her family.

Vellanki et al. AACE 2015; 1(2)::e123-e126.


A case of atypical type 1 DM?

•  The patient was a 31-year-old Caucasian female who had been diagnosed with T1D at the age of 5 and treated with insulin thereafter. Her T1D was complicated by retinopathy and nephropathy, and she developed end-stage renal disease in her 20s. During the evaluation, her C-peptide level was found to be 7.32 ng/mL (normal range, 0.8–3.9). Her family history was significant for T1D in her brother and mother, as well as multiple members on the maternal side of her family.

Vellanki et al. AACE 2015; 1(2)::e123-e126.

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Maturity Onset Diabetes of the Young

Autosomal dominant diabetes, usually before 25 years old 80% are misdiagnosed!

MODY1 HNF4A MODY2 GCK MODY3 HNF1A MODY4 PDX1 MODY5 HNF1B MODY6 NEUROD1 MODY7 KLF11 MODY8 CEL MODY9 PAX4 MODY10 insulin MODY11 BLK MODY12 ABCC8 MODY13 KCNJ11


It does it matter to know if you have MODY

Pearson et al. Lancet 2003; 362(9392):1275-1281.

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Mechanism?

•  MODY3 patients have increased sensitivity to sulfonylurea, lower insulin resistance compared to type 2 patients.

•  MODY1 patients respond well to sulfonylurea therapy as well.

•  Unfortunately, there is progressive beta cell decline and eventual need for insulin.


Another case of atypical type 1?

•  This is a 20-year-old male, the product of a consanguineous marriage. He had a diagnosis of T1DM at the age of 8 years and complained from visual deficiency since early infancy. Ophthalmologic examination disclosed bilateral optic atrophy. In addition, hearing loss, diabetes insipidus and neurogenic bladder were recognized. He has a younger brother also with T1DM in whom a subsequent funduscopic examination revealed bilateral optic atrophy.

Blanco-Aguirre et al. Gene 566(1):63-67

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Case 1

•  This is a 20-year-old male, the product of a consanguineous marriage. He had a diagnosis of T1DM at the age of 8 years and complained from visual deficiency since early infancy. Ophthalmologic examination disclosed bilateral optic atrophy. In addition, hearing loss, diabetes insipidus and neurogenic bladder were recognized. He has a younger brother also with T1DM in whom a subsequent funduscopic examination revealed bilateral optic atrophy.

Blanco-Aguirre et al. Gene 566(1):63-67


Diabetes Insipidus Diabetes Mellitus Optic Atrophy Deafness

1:500,000

~ 200 reported cases

90% have mutations in WFS1

Wolfram syndrome -- another rare cause of diabetes

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WFS1 is a endoplasmic reticulum (ER) resident protein

Rohayem et al. Diabetes Care 34(7):1503-1510


Beta cells are insulin producing factories

In each cell, 1 million insulin molecules are made per minute!

Chan et al. Trends in Mol Med 2003; 9(10):430-435

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Cells try to fix things when their ER’s are overwhelmed

Papa, Oakes, Ann Rev Path 2015; 10:173-194


WFS1 regulates endoplasmic reticulum stress

Shang et al. Diabetes 2014; 63(3):923-933

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Model – Wfs1 function

Wfs1 loss


A drug that inhibits the terminal UPR improves diabetes in mice

Ghosh et al. Cell 2014; 158(3):534-549

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Mild ER stress may signal beta cell proliferation through homeostatic UPR

Sharma et al. JCI 2015; 125(10):3831-3846


Modulation of UPR might be a future diabetes therapeutic target

Sharma et al. JCI 2015; 125(10):3831-3846

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Other examples of inherited beta cell dysfunction

•  Maternally inherited diabetes and deafness: – Discovered 1992, defect in insulin secretion – 70-80% of the time also have a maculopathy

•  Clues: – Deafness and diabetes “complications” out of

proportion


MIDD is caused by a mitochondrial DNA mutation encoding a tRNA

•  The mitochondrial genome is passed maternally.

•  Since each egg has many mitochondria, only some subset may have the mutation (heteroplasmy).

•  This can lead to variable penetrance.

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MIDD is caused by a mitochondrial DNA mutation

•  Hypothesis: Decreased mitochondrial function will lead to

reduced glucose stimulated insulin secretion.


MIDD is caused by a mitochondrial DNA mutation

•  Why this specific mutation causes

diabetes is not clear since other mutations that affect mitochondria do not cause diabetes.

•  Avoid statins, metformin.

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Beta cells fail in type 2 diabetes: introduction

Cobelli et al. Am J Phys Endo Metab 2007 293(1):E1-E15)


Impaired insulin secretion in type 2 diabetics

Gerich, Diabetes 51(suppl 1):S117-S121, 2007

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Reduced beta cell mass in type 2 diabetics

Butler et al., Diabetes 2003; 50(1):102-11


Beta cell failure is essential for type 2 diabetes

(Prentki, JCI, 2008)

normal glucose

tolerance

impaired glucose

tolerance diabetic

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Genome wide association studies and type 2 DM


Genome wide association studies implicate the beta cell in type 2 DM

•  Around 88 regions identified. •  Most loci are thought to work through the beta cell.

•  Wfs1 (Wolfram syndrome) •  Slc30a8 (Zinc transporter) •  Glucokinase (remember MODY2?)

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Type 2 diabetes GWAS

(Billings and Florez, Ann NY Acad Sci 2010 1212:59-77)


Progression of type 2 diabetes

Festa et al. Diabetes 2006;55(4):1114-20

Insulin resistance atherosclerosis study

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Kahn et al. NEJM 2006;355:2427-2443



Kahn et al. NEJM 2006;355:2427-2443

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Kahn et al. NEJM 2006;355:2427-2443


Could GLP-1 agonists be the solution?

Farilla et al. Endocrinology 2002; 143(11):

•  Zucker fatty rat •  2 days of continuous

infusion of Glp-1 •  Most studies are < 2

weeks

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Park et al. Diabetologia 2013;56(3):508-519

GLP-1 agonists improve beta cell function in human islets in vitro


GLP-1 agonists can improve beta cell survival in vitro

Park et al. Diabetologia 2013;56(3):508-519

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liraglutide

GLP-1 agonists can improve beta cell function in vivo

Chang et al. Diabetes 2003, 52(7):1786-91

vehicle


Do GLP-1 agonists increase beta cell mass?

There is no data. But, if there was an increase in beta cell mass, we would hope for less progression of diabetes.

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Long term GLP-1 agonists still appear to fail…

Exena2de 40% dropout rate

Wysham et al. 2015, Mayo Clinic Proceedings 90(3):356-365


The effect is mostly on resistance

Exenatide + metformin, 3 years

Bunck, Diabetes Care 2011, Sep; 34(9):2041-2047

3 years exenatide

Baseline exenatide

baseline lantus

3 years lantus

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Short term liraglutide improves human islets transplanted into mice

Abdulreda et al. Cell Metab; 2016, in press


Long term liraglutide can cause beta cell failure (in mice)

Abdulreda et al. Cell Metab; 2016, in press

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Conclusion

•  No clear evidence that GLP-1 agonists can improve beta cell mass or long term function despite promising data in vitro and some short term data in rodents.

•  Perhaps, the clearest evidence would be durability of response in humans. This is not clear.


Summary

•  The beta cell is critical to the pathogenesis of diabetes mellitus.

•  Improving beta cell function and mass in the long term would seem to be a reasonable goal of future therapies.

•  However, it is not clear if any existing therapeutics affect beta cell mass or prevent a potential decline in function.

Documents

Islet Function and the Treatment of Diabetes