3/17/16
1
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
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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?
3/17/16
2
diabetes.ucsf.edu a history of innova-on…a vision of a cure
The pancreatic islet
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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
3/17/16
3
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Type 1 diabetes: autoimmune beta cell destruction
glucagon anti-CD3
Itoh et al., JCI 1993; 92:2313.
Pancreas biopsies from new type 1 diagnoses
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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
3/17/16
4
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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.
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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.
3/17/16
5
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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
diabetes.ucsf.edu a history of innova-on…a vision of a cure
It does it matter to know if you have MODY
Pearson et al. Lancet 2003; 362(9392):1275-1281.
3/17/16
6
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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.
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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
3/17/16
7
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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.ucsf.edu a history of innova-on…a vision of a cure
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
3/17/16
8
diabetes.ucsf.edu a history of innova-on…a vision of a cure
WFS1 is a endoplasmic reticulum (ER) resident protein
Rohayem et al. Diabetes Care 34(7):1503-1510
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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
3/17/16
9
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Cells try to fix things when their ER’s are overwhelmed
Papa, Oakes, Ann Rev Path 2015; 10:173-194
diabetes.ucsf.edu a history of innova-on…a vision of a cure
WFS1 regulates endoplasmic reticulum stress
Shang et al. Diabetes 2014; 63(3):923-933
3/17/16
10
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Model – Wfs1 function
Wfs1 loss
diabetes.ucsf.edu a history of innova-on…a vision of a cure
A drug that inhibits the terminal UPR improves diabetes in mice
Ghosh et al. Cell 2014; 158(3):534-549
3/17/16
11
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Mild ER stress may signal beta cell proliferation through homeostatic UPR
Sharma et al. JCI 2015; 125(10):3831-3846
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Modulation of UPR might be a future diabetes therapeutic target
Sharma et al. JCI 2015; 125(10):3831-3846
3/17/16
12
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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.
3/17/16
13
diabetes.ucsf.edu a history of innova-on…a vision of a cure
MIDD is caused by a mitochondrial DNA mutation
• Hypothesis: Decreased mitochondrial function will lead to
reduced glucose stimulated insulin secretion.
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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.
3/17/16
14
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Beta cells fail in type 2 diabetes: introduction
Cobelli et al. Am J Phys Endo Metab 2007 293(1):E1-E15)
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Impaired insulin secretion in type 2 diabetics
Gerich, Diabetes 51(suppl 1):S117-S121, 2007
3/17/16
15
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Reduced beta cell mass in type 2 diabetics
Butler et al., Diabetes 2003; 50(1):102-11
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Beta cell failure is essential for type 2 diabetes
(Prentki, JCI, 2008)
normal glucose
tolerance
impaired glucose
tolerance diabetic
3/17/16
16
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Genome wide association studies and type 2 DM
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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?)
3/17/16
17
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Type 2 diabetes GWAS
(Billings and Florez, Ann NY Acad Sci 2010 1212:59-77)
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Progression of type 2 diabetes
Festa et al. Diabetes 2006;55(4):1114-20
Insulin resistance atherosclerosis study
3/17/16
18
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Progression of type 2 diabetes
Kahn et al. NEJM 2006;355:2427-2443
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Progression of type 2 diabetes
Kahn et al. NEJM 2006;355:2427-2443
3/17/16
19
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Progression of type 2 diabetes
Kahn et al. NEJM 2006;355:2427-2443
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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
3/17/16
20
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Park et al. Diabetologia 2013;56(3):508-519
GLP-1 agonists improve beta cell function in human islets in vitro
diabetes.ucsf.edu a history of innova-on…a vision of a cure
GLP-1 agonists can improve beta cell survival in vitro
Park et al. Diabetologia 2013;56(3):508-519
3/17/16
21
diabetes.ucsf.edu a history of innova-on…a vision of a cure
liraglutide
GLP-1 agonists can improve beta cell function in vivo
Chang et al. Diabetes 2003, 52(7):1786-91
vehicle
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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.
3/17/16
22
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Long term GLP-1 agonists still appear to fail…
Exena2de 40% dropout rate
Wysham et al. 2015, Mayo Clinic Proceedings 90(3):356-365
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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
3/17/16
23
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Short term liraglutide improves human islets transplanted into mice
Abdulreda et al. Cell Metab; 2016, in press
diabetes.ucsf.edu a history of innova-on…a vision of a cure
Long term liraglutide can cause beta cell failure (in mice)
Abdulreda et al. Cell Metab; 2016, in press
3/17/16
24
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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.
diabetes.ucsf.edu a history of innova-on…a vision of a cure
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.