Literature seminar

Diabetes treatment and latest research
M2 Sachie Murata
2019/10/31

Contents

1. Introductionn Recent trend
n Types of Diabetesn Main etiology

2. Treatment and latest research for Diabetes
n Incretin-based anti-diabetic drugs
n Adiponectin as the innovative drug development target
n GPR119 as a drug target of new oral hypoglycemic agent
n Diabetes research for the insight of epigenome

3. Summary

What is Diabetes ?

ü Metabolic disorders characterized by high blood sugar levels over a prolonged period.
ü Diabetes can cause many complications.
( cardiovascular disease, stroke, chronic kidney disease, foot ulcers, and damage to the eyes etc.)

ü Diabetes at least doubles a person's risk of early death.

https://time.com/5183350/diabetes-five-types/

Trend of diabetes in the worldü Estimated 425 million people had diabetes worldwide (2017).
ü The number of patients in Asia and Africa is expected to increase.

Middle east & North Africa
North America & caribbean
South & central America
South East Asia
Western pacific

IDF DIABETES ATLAS Eighth edition 2017

Diabetes Complications
ü Complications such as myocardial infarction, stroke, lower limb amputation, kidney disease, andhyperglycemia are known to occur.
ü Reductions in a diverse spectrum of diabetes-related complications were captured in a 2014 study.

Diabetes Care 2017, 40(10), 1289-129

Types of diabetes
n Type I diabetes:
This type occurs when the body fails to produce insulin. People with type I diabetes areinsulin-dependent, which means they must take artificial insulin daily to stay alive.

n Type 2 diabetes:
Type 2 diabetes affects the way the body uses insulin. While the body still makes insulin, unlike intype I, the cells in the body do not respond to it as effectively as they once did. This is the mostcommon type of diabetes,and it has strong links with obesity.

n Gestational diabetes:
This type occurs in women during pregnancy when the body can become less sensitive to insulin.
Gestational diabetes does not occur in all women and usually resolves after giving birth.

Main etiology
Diabetes

Type I diabetes

Pancreatic βcell destruction
by autoimmunity

Type 2 diabetes

Islet cell injury
by virus

Insulin resistanceIslet dysfunction

Pancreatic islets: The β-cells of the pancreatic islets secrete insulin and regulate
glucose level.

https://en.wikipedia.org/wiki/Pancreatic_islets

Contents

1. Introductionn Recent trend
n Types of Diabetesn Main etiology

2. Treatment and latest research for Diabetes
n Incretin-based anti-diabetic drugs
n Adiponectin as the innovative drug development target
n GPR119 as a drug target of new oral hypoglycemic agent
n Diabetes research for the insight of epigenome

3. Summary

Treatment (Incretin-based anti-diabetic drugs)
Incretin(Intestine secretion insulin)a group of metabolic hormones that stimulate a decrease in blood glucose levels.
Incretins are released after eating and augment the secretion of insulin released frompancreatic β-cells of the islets of Langerhans by a blood glucose dependent mechanism.
（GIP、GLP-1）

GLP-1：glucogan-likepeptide-1
GIP：glucose-dependent insulinotropic polypeptide

In particular, drugs targeting GLP-1 and GLP-1 receptor are used in the treatment of diabetes.

Treatment (Incretin-based anti-diabetic drugs)
GLP-1 receptor agonists (GLP-1RA)n enhance glucose- dependent insulin
secretion by mimicking theglucoregulatory effects of endogenous
GLP-1 and by providing pharmacological(high) levels of GLP-1 activity, and also
suppress glucagon releaseDPP-4 inhibitorsn prevent enzymatic inactivation ofendogenous GLP-1, resulting in
prolonged availability of physiologicallevels of native GLP-1 and GIP andmodest receptor activation

Adv Ther, 2014, 31, 289–317

Treatment (Incretin-based anti-diabetic drugs)
GLP-1 receptor agonists (7-37)

Proteolytic cleavage (DPP4)

n Stability against DPP4n Long plasma half-life

DPP-4 inhibitors

sitagliptin

Clin Pharmacokinet, 2016, 55, 657–672
Spectrochim. Acta A Mol. Biomol. Spectrosc,2019 , 223 , 117286

Contents

1. Introductionn Recent trend
n Types of Diabetesn Main etiology

2. Treatment and latest research for Diabetes
n Incretin-based anti-diabetic drugs
n Adiponectin as the innovative drug development target
n GPR119 as a drug target of new oral hypoglycemic agent
n Diabetes research for the insight of epigenome

3. Summary

Treatment (Adiponectin as the innovative drug development target)Impaired Adiponectin Action Is a Hallmark of Obesity- Related Diseases

Adiponectin: protein hormone which is involved inregulating glucose levels as well as fatty
acid breakdown.
Function- Glucose uptake promoting action without
insulin receptor- fatty acid burning- increase insulin receptor sensitivity- Increased insulin sensitivity- suppression of arteriosclerosis- anti-inflammatory- suppression of myocardial hypertrophy

Cell Metab. 2013, 17, 185-96

Treatment (Adiponectin as the innovative drug development target)
Impaired Adiponectin Action Is a Hallmark of Obesity- Related Diseases

Adiponectin: protein hormone which is involved inregulating glucose levels as well as fatty
acid breakdown.

ü Decreased adiponectin effects cause
various types of obesity-related diseases.

Cell Metab. 2013, 17, 185-96

Treatment (Adiponectin as the innovative drug development target)
Strategies to Increase Adiponectin Effects and Pathophysiological Roles of Adiponectin/AdipoR in Obesityn Injection of adiponectin itself
n Upregulation of adiponectinn Adiponectin receptor agonistn Upregulation of AdipoR

Cell Metab. 2013, 17, 185-96

Treatment (Adiponectin as the innovative drug development target)
Translational Research Targeted to Adiponectin and AdipoRs

AdipoR agonists such as AdipoRon are a promisingtherapeutic approach for the treatment of obesity-relateddiseases such as type 2 diabetes.
Nature, 2013, 503, 493-499

Contents

1. Introductionn Recent trend
n Types of Diabetesn Main etiology

2. Treatment and latest research for Diabetes
n Incretin-based anti-diabetic drugs
n Adiponectin as the innovative drug development target
n GPR119 as a drug target of new oral hypoglycemic agent
n Diabetes research for the insight of epigenome

3. Summary

Treatment (GPR119 as a drug target of new oral hypoglycemic agent)
Proposed mechanisms of GPR119 agonist action
GPR119 ：regulate incretin and insulin
hormone secretion.

British Journal of Pharmacology, 2008, 153, S76–S81

Treatment (GPR119 as a drug target of new oral hypoglycemic agent)TAK-875

AR231453

PSN-632408

MBX-2982
GPR119 agonist can stimulate secretion of endogenous GLP-1 ,and give improved
glycaemic control and associated weight loss through an oral dosing regime.Diabetes research from the insight of epigenomen Type 2 diabetes is fundamentally a heterogeneous disease.
n To what extent do genetic and environmental factors contribute to its pathogenesis?
n To what extent do insulin resistance and islet insufficiency contribute to the condition?
n How likely are individuals to develop complications?

Large individual differences

Personalized medicine？

Contents

1. Introductionn Recent trend
n Types of Diabetesn Main etiology

2. Treatment and latest research for Diabetes
n Incretin-based anti-diabetic drugs
n Adiponectin as the innovative drug development target
n GPR119 as a drug target of new oral hypoglycemic agent
n Diabetes research for the insight of epigenome

3. SummaryDiabetes research from the insight of epigenome
JMJD1A：(Jumonji domain-containing 1a)n The H3K9-specific demethylase.
n It has an important role in nuclear hormone receptor-mediated gene activation and male germ celldevelopment.

化学と⽣物, 2014, Vol. 52, No. 4

Diabetes research from the insight of epigenome
Jhdm2a=JMJD1A

The loss of Jhdm2a function results in abnormal fat metabolism and obesity.
⇦Abnormal fat accumulaIon inorgans of Jhdm2a2/2 mice

Jhdm2a knockout

wild-type（7-month-old littermates）
Nature, 2009, 458, 757–761

Diabetes research from the insight of epigenome
Jhdm2a=JMJD1A

n Serum free fatty acid (FFA)n Triglyceride (TG)n Total cholesterol (TCHO)ü The increased levels of FFA,TG,and TCHO were observed.

ü Growth curve of littermates fed with ahigh-fat diet (HFD) or normal chow
Nature, 2009, 458, 757–761

Diabetes research from the insight of epigenome
Jhdm2a=JMJD1A

Mice with abnormal methylation with histone H3K9 show obesity insulin resistance.

ü Whole-body insulin insensitivity is associated with adult onset obesity JHDM2a-/- mice.
ü These mice mimic a pre-diabetic state.

It became clear that the mouse exhibits a characteristic of the human metabolic syndrome.
Genes to Cells, 2009, 14, 991–1001

Diabetes research from the insight of epigenome
Jhdm2a=JMJD1A

JMJD1A：JMJD1A regulates β-adrenergic-induced systemic metabolism and body weight control.

Nat Com, 2015 ,6 , 7052

Diabetes research from the insight of epigenome
Jhdm2a=JMJD1A
BAT:Brown adipose tissue
scWAT: subcutaneous white adipose tissuen In BAT, Ucp1 locus is in euchromatinn Cold exposure leads to acute induction of Ucp1 mRNA
through the mechanisms independent of H3K9me2
demethylation.

n In scWAT, Usp1 locus is in heterochromatin with H3K9me2
n H3K9me2 at Ucp1 gene locus needs to be removed for beige
adipogenesis.
Nat. com., 2018, 9, 1566

Diabetes research from the insight of epigenome
Jhdm2a=JMJD1A
Phospho-S265 JMJD1A induces beige biogenesis

n A 4℃ treatment induced the expression of the core set of thermogenic genes in scWAT, including
Ucp1, Cidea, Pgc1a, Cox8b, Elovl3, and Dio2 in WT mice.

Nat. com., 2018, 9, 1566

Diabetes research from the insight of epigenome
Jhdm2a=JMJD1A

p265-JMJD1A-PPARγ-PGC1α-PRDM16 protein complex

n β-adrenergic signaling mediates the formation of a multi-protein
complex containing JMJD1A-PPARγ-PGC1α-PRDM16.
n Phosphorylation of S265 in JMJD1A nucleates formation of the entire
complex.
n These are essential for beige-selective gene induction in scWAT.

Nat. com., 2018, 9, 1566

Diabetes research from the insight of epigenome
Jhdm2a=JMJD1A

Hypothetical model
Step1
β-adrenergic signal leads to phosphorylation of JMJD1A
Step1,top
JMJD1A triggers the formation of a PRDM16-PGC1α-PPARγtranscription complex that targets beige-selective genes
Step2
JMJD1A then demethylates H3K9me2 to turn on thetranscription of these genes in scWAT.

Nat. com., 2018, 9, 1566

Diabetes research from the insight of epigenome
Jhdm2a=JMJD1A
Complementary mechanisms for thermogenic geneinduction in acute and chronic cold stressNat. com., 2018, 9, 1566

Contents

1. Introductionn Recent trend
n Types of Diabetesn Main etiology

2. Treatment and latest research for Diabetes
n Incretin-based anti-diabetic drugs
n Adiponectin as the innovative drug development target
n GPR119 as a drug target of new oral hypoglycemic agent
n Diabetes research for the insight of epigenome

3. Summary

Summaryn Diabetes has various types of serious complications.
n Various strenuous studies have been conducted to overcome diabetes.
n There are individual differences such as ineffectiveness of existing therapies when various
complications occur.
n Diabetes mellitus is a disease that still has many medical unmet medical needs, and research toeliminate unmet medical needs and the development of new therapies are indispensable fields.
n Clarifying the protein that regulates phosphorylation of JMJD1A is expected to provide important
knowledge for the development of treatments for diabetes.

Appendix

Natural History of Type 2 Diabetes

Treatment (Adiponectin as the innovative drug development target)
Translational Research Targeted to Adiponectin and AdipoRs

Cell Metab. 2013, 17, 185-96

Diabetes research from the insight of epigenome

Cell Metab, 2018, 27, 1121–1137

Diabetes research from the insight of epigenome
Phospho-S265 JMJD1A induces beige biogenesis

n Basal whole-body oxygen consumption rate (OCR) before NE injection was significantly higher in the
4 ℃- acclimated WT mice.
n OCR response was 20–25% lower in Jmjd1a-S265AKI/KI mice, relative to WT mice.
Nat. com., 2018, 9, 1566