Diabetes: Diagnosis, Treatment, and Opportunities

Module 5: Frontiers and New Horizons

Michael German, MD Professor of Medicine UC San Francisco

Birth and Death of the Beta Cell

Introduction: Michael German, MD o Dr. Michael German, Professor of Medicine,

Clinical Director of the UCSF Diabetes Center o Teaches Diabetes, Endocrinology and Metabolism to students, residents, fellows and patients. o Directs a research program on the biology of the pancreatic beta cell.

Lear ning Objectives

o The importance of beta-cell mass in diabetes o The origins of beta cells during development and in adult patients o Signals that control beta cell numbers o Challenges in increasing beta cell mass o Future approaches to beta cell mass expansion

The Pancreatic Beta Cell

Michael German, MD

Role of the Beta Cell in Diabetes

o Type 1 diabetes: Absolute beta cell deficiency
o Type 2 diabetes: Relative beta cell deficiency due to inadequate beta cell mass or function usually in the face of increased insulin demand
Michael German, MD

Where Do Beta Cells Come From?

Michael German, MD

The Pancreatic Beta Cell

Metabolic
Glucose Lipids

Auto/Paracrine

Islet

ATP Adenosine Serotonin Dopamine Acetylcholine

Insulin IAPP IGF2 NPY Ucn3 GABA VEGF PDGFa

Adrenal (cortisol, epinephrine) Adipose (leptin, adiponectin) Gut (GLP1, GIP, gastrin) Bone (osteocalcin) Liver (betatrophin) Pituitary (GH, Prl) Placenta (PL) Endocrine

Parasympathetic Sympathetic Sensory Enteric

Neural
Michael German, MD

When Does Beta Cell Mass Change?

o Expansion:
Perinatal Pregnancy Obesity

o Contraction
Postpartum Starvation Insulinoma
Michael German, MD

The Beta Cell during Pregnancy

Placenta
-cell
PRLR TPH Trp
HTR2B

5HT

proliferation
Michael German, MD

The Beta Cell during Pregnancy

Placenta
-cell
PRLR TPH Trp
HTR1D

5HT

proliferation
Michael German, MD

The Pancreatic Beta Cell

Metabolic
Glucose Lipids

Auto/Paracrine

Islet

ATP Adenosine Serotonin Dopamine Acetylcholine

Insulin IAPP IGF2 NPY Ucn3 GABA VEGF PDGFa

Adrenal (cortisol, epinephrine) Adipose (leptin, adiponectin) Gut (GLP1, GIP, gastrin) Bone (osteocalcin) Liver (betatrophin) Pituitary (GH, Prl) Placenta (PL) Endocrine

Parasympathetic Sympathetic Sensory Enteric

Neural
Michael German, MD

How Do We Apply This to Patients?

o Beta cell expansion is especially critical in pregnancy and the perinatal period. o Drugs that impact beta cell proliferation and death. o Environmental factors that impact beta cell proliferation and death.
Michael German, MD

Challenges to Human Application?

o Limitations in our knowledge of human beta cell turnover.
All based on pathologic samples No way to measure beta cell mass, proliferation or death in humans in vivo.

o No clear evidence that any current therapies either protect or expand beta cell mass in humans
Michael German, MD

How Do We Apply This to Patients?

o Beta cell replacement. o Beta cell protection. o Beta cell expansion in vitro. o Beta cell expansion in vivo.

Michael German, MD

The Pancreatic Beta Cell

Metabolic
Glucose Lipids

Auto/Paracrine

Islet

ATP Adenosine Serotonin Dopamine Acetylcholine

Insulin IAPP IGF2 NPY Ucn3 GABA VEGF PDGFa

Adrenal (cortisol, epinephrine) Adipose (leptin, adiponectin) Gut (GLP1, GIP, gastrin) Bone (osteocalcin) Liver (betatrophin) Pituitary (GH, Prl) Placenta (PL) Endocrine

Parasympathetic Sympathetic Sensory Enteric

Neural
Michael German, MD