Pathogenesis of type 2 diabetes in Japan and East Asian populations: Basic and clinical explorations

Abstract

It is now accepted that the pathogenesis of type 2 diabetes in East Asians including Japanese differs distinctly from that in Caucasians. Many non-obese individuals in Japan develop type 2 diabetes and present clinically with insufficient insulin secretion rather than a large increase in the insulin resistance. To understand the pathophysiology of this non-obese diabetes, we studied Goto-Kakizaki rats, a unique model of spontaneous non-obese diabetes, and identified mitochondrial dysfunction in pancreatic β-cells as a factor in decreased insulin secretion. Looking for a clinical treatment option, we focused on the incretins because of their glucose-dependent insulin stimulatory effect. Our findings have contributed to the understanding of incretin action and the development of incretin-associated therapeutics and shed light on the nature of East Asian diabetes and its optimal clinical treatment.

1. Introduction

Diabetes is a chronic disease requiring long-term clinical management to prevent the development and progression of complications. The number of people with type 2 diabetes (T2D) continues to rise worldwide, making it a major non-communicable health problem. It is now widely accepted that lifestyle and genetics both are factors in the etiology of T2D. T2D can develop with distinct but interrelated pathologies: differing degrees of increased insulin resistance and decreased insulin secretion. In the 1960s and early 1970s, as diabetes with manifest obesity was the predominant presentation of the disease in Western countries, the model of its development emphasized increased insulin resistance as the proximate cause of onset. Development of the Zucker fatty rat model of obesity-induced diabetes with increased insulin resistance furthered this concept, which became mainstream in clinical and basic research investigations. Thus, in contrast to type 1 diabetes, which results from total or near-total β-cell destruction, T2D was understood to be the result of insulin resistance due to excess adipose tissue compensated by excessive insulin secretion, leading to β-cell dysfunction as a secondary factor and subsequent hyperglycemia.

Problematic for this model, the body mass index (BMI) in the Japanese population with diabetes resembles that in those without the disease, which is about 22-23. In fact, obesity in Japan is rare and individuals with diabetes and normal BMI frequently present clinically with the disease, suggesting a distinct etiology. Indeed, our original oral glucose tolerance test (OGTT) evaluation of insulin secretion in healthy Japanese indicated that it was only about half that in the US population, strongly suggesting the possibility of low insulin secretion as a trigger of the disease in this population (Fig. 1).¹⁾ Furthermore, the insulinogenic index (Δinsulin/Δglucose at 30 min after OGTT) in Japanese individuals was found to be generally lower than that in Caucasians, further implicating impaired insulin secretion as a possible trigger of onset in these non-obese individuals. This hypothesis was at first discounted by Western researchers, so far as to suggest that we may have confounded our patients’ disease with type 1 diabetes. Subsequent studies in support of our hypothesis were reported from Korea and China as well as other Asian countries.^2),3) It has now become accepted in the field of diabetes research and treatment that the pathophysiology of the disease in East Asian individuals differs in this crucial regard from that in Western populations. In consideration of these findings, we have continued to focus on this insulin secretory defect in response to glucose and the development of specifically appropriate therapeutic agents.

Fig. 1

(Color online) Insulin secretion by oral glucose intake in Caucasian (right panel) and Japanese (left panel). Insulin response after oral glucose intake in Caucasian and Japanese with normal glucose tolerance (NGT) and type 2 diabetes (T2D) (superimposed from a figure in Seino et al. (1975)¹⁾ and Yalow and Berson (1960),⁴⁾ respectively).

2. Section

Increasing awareness of the distinct phenotype of Japanese type 2 diabetes.

When we first suspected in the 1970s that Japanese T2D might result from lower insulin secretory capacity, most of the extant evaluations were those of Caucasians whose diabetes resulted from insulin resistance due to obesity (BMI ＞ 30).⁴⁾ However, the BMI of the Japanese who we examined was found to be about 22-23, raising the possibility that the insulin levels in our study might reflect only differing BMI and adiposity. We therefore compared insulin resistance and insulin secretory capacity in Japanese with those established in Caucasians, whose average BMI reported in the Botnia study was close to 26, the lowest BMI in that study of Western populations.^5),6) Even so, comparison of the changes in insulin resistance and β-cell function between normal glucose tolerance (NGT) and diabetes in Japanese and Caucasians revealed a significantly lesser incline in the former and a significantly greater decline in the latter, clearly bolstering our hypothesis (Fig. 2).

Fig. 2

Insulin resistance (HOMA-IR) and insulinogenic index in Caucasian and Japanese. Comparison of homeostatic assessment insulin resistance (HOMA-IR) and insulinogenic index in Caucasian and Japanese with NGT and T2D (referenced from Fukushima et al. (2004)⁹⁾).

This characteristic may well account for the distinct phenotype of T2D seen in East Asians. Investigation of a subtype of early-stage diabetes called isolated post-challenge hyperglycemia (IPH), which is defined as fasting plasma glucose level ＜ 7 mmol/L (126 mg/dL) and 2-h plasma glucose level ≥ 11.1 mmol/L (200 mg/dL), showed that Japanese patients with IPH exhibit impaired early-phase insulin secretion and little insulin resistance, suggesting insufficient insulin secretory capacity as the triggering factor in T2D in Japanese.⁷⁾ Our investigation using OGTT revealed that a large proportion of pre-diabetes in Japanese can be classified as impaired glucose tolerance (IGT), which is characterized by a pronounced postprandial glycemic rise. The prevalence of IGT was 70-80％ and that of impaired fasting glucose (IFG) was 20-30％ in Japanese, whereas the prevalence of IGT and IFG in the Botnia study were about half the values (Fig. 3).^5),8),9) These studies consistently pointed to a distinct pathophysiology of diabetes in East Asia.

Fig. 3

Prevalence of impaired glucose tolerance and impaired fasting glucose in Caucasian and Japanese. The prevalence rates were calculated from Tripathy et al. (2000)⁵⁾ and Fukushima et al. (2004).⁹⁾ NGT, normal glucose tolerance; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IGT/FH, impaired glucose tolerance glucose with fasting hyperglycemia.

Pancreatic β-cell dysfunction in a non-obese diabetes model.

There are few animal models of non-obese diabetes due to β-cell dysfunction rather than complete β-cell loss. Goto-Kakizaki (GK) rats are a model of non-obese diabetes that was established by mating rats that showed higher postprandial blood glucose elevation by OGTT.¹⁰⁾ Isolated islets from GK rats were found to consistently exhibit less glucose-stimulated insulin secretion than wild-type lines. Indeed, the precise mechanism of insulin secretion in GK rats served to clarify the phenotype of non-obese T2D. We initially examined using patch-clamp analysis the KATP channels in isolated pancreatic β-cells of GK rats, which exhibited significantly less sensitivity to glucose elevation than that in wild-type rats,¹¹⁾ as expected. However, the ATP sensitivity of KATP channels of GK rats resembled that of wild-type rats, suggesting a defect in ATP production in response to glucose. Therefore, we suspected mitochondrial dysfunction, and dihydroxyacetone (DHA), which enhances the glycerol-phosphate shuttle to increase cellular ATP levels, was administered. DHA stimulates insulin secretion and promotes ATP independent of glucose in wild-type β-cells. However, enhancement of insulin secretion was significantly diminished in GK rat β-cells, suggesting deterioration of the glycerol-phosphate shuttle (Fig. 4).¹²⁾ Indeed, early phase insulin secretion is triggered by closure of the KATP channels in response to an increased ATP concentration, which is influenced by ATP production and the pyruvate kinase pathway. Thus, this series of studies of GK rats demonstrated that impaired mitochondrial function may result in impairment of early phase insulin secretion.

Fig. 4

(Color online) Hypothetical model of mitochondrial dysfunction in GK rat pancreatic β-cells. Due to deterioration of the glycerol-phosphate shuttle, ATP production via the TCA cycle is reduced. Local ATP production by plasma membrane-associated enzymes (including pyruvate kinase) is intact. The use of pyruvate in the TCA cycle in mitochondria may be reduced in GK rats, potentially leading to increased lactate production.

Incretin signaling affects not only β-cell activity but also many other physiological processes.

The pathophysiological difference between non-obese diabetes with a triggering decrease in insulin secretory capacity and obese diabetes with a triggering increase in insulin resistance drastically influences the optimal clinical treatment of T2D. Indeed, sulfonylureas have been preferably used as insulin secretagogues in Japan, whereas biguanides have been the first-line treatment for T2D in Western countries. However, sulfonylureas primarily lower fasting blood glucose levels and are not optimal for improving early phase insulin secretion. Although glinides can enhance postprandial insulin secretion, there is increased risk of hypoglycemia.

The physiological process through which insulin secretion is increased proportionally to the amount of ingested carbohydrate is known as the entero-insular axis. In 1929, La Barre’s group demonstrated that a purified product from the intestinal tract lowered blood glucose, which they termed intestine secretion insulin (INCRETIN).¹³⁾ Incretin is an attractive target for improving early phase insulin secretion without increasing the risk of hypoglycemia.

Incretin had not been described at the molecular level before 1970 when Brown et al. cloned gastric inhibitory polypeptide (GIP). They showed that GIP administered simultaneously with glucose via an intravenous route stimulated more insulin secretion than glucose alone, and they appropriately re-named the acronym GIP as glucose-dependent insulinotropic polypeptide,^14),15) but it remained unclear whether the GIP effect on insulin secretion was direct or not. Using GIP prepared by complete synthesis in isolated islets, we demonstrated that GIP directly stimulates insulin and glucagon secretion in a glucose-dependent manner in vitro, establishing that GIP is itself an incretin.¹⁶⁾ In the 1970s, we unexpectedly found that Japanese patients with T2D had an impaired GIP-insulin axis, the mechanism of which remains to be elucidated.¹⁷⁾ We then used a molecular biological approach and cloned human GIP cDNA and described the structures of both the human GIP gene and the human GIP receptor gene.^18)-20) Following the discovery of the insulinotropic effect of glucagon-like peptide-1 (GLP-1), the other incretin, in the early 1980s, incretin research accelerated.²¹⁾ By investigating GIP receptor knockout mice and GIP/GLP-1 receptor double knockout mice, we elucidated that both GIP and GLP-1 are required in the early phase of the insulin secretory response to glucose ingestion, demonstrating that both of the incretins are critical in the control of postprandial glycemia in vivo.²²⁾

We subsequently explored various feeding conditions and found that ablation of the GIP receptor in high-fat-fed mice almost completely eliminated the expected obesity and that GIP increased nutrient uptake into adipocytes.²³⁾ This was the first demonstration of the physiological extra-pancreatic action of incretin. Later, various extra-pancreatic effects of the incretins in other tissues such as bone, peripheral nerves, and the heart were identified (Table 1).^23)-35) Suppression of the brain appetite center and delayed gastric emptying are also now recognized as beneficial, extra-pancreatic effects of clinical GLP-1 receptor agonist therapy.³⁶⁾

Table 1

Role of the incretins in the various tissues

	Tissues	Roles	References (contributed by our group)
GIP	Nerves	Neuropathy	J. Diabetes Investig. (2014)24)
	Heart	Myocardial infraction	Cell Metab. (2018)25)
	Artery	PAD	Endocrinology (2018)26)
	Fat	Fat accumulation	Nat. Med. (2002)23)
			Biochem. Biophys. Res. Commun. (2007)27)
			J. Biol. Chem. (2011)28)
			Biochem. Biophys. Res. Commun. (2019)29)
	Bone	Bone metabolism	Mol. Endocrinol. (2006)30)
	Sperm	Sperm movement	Endocrinology (2017)31)
GLP-1	Nerves	Neuropathy	Diabetes (2011)32)
	Nephropathy	Nephropathy	Kidney Int. (2014)33)
			Kidney Int. (2016)34)
	Bone	Bone metabolism	Endocrinology (2008)35)

The secretion of incretins (GLP-1 and GIP) might be different between Asians and Caucasians, although a direct comparison has not been done.^37),38) The ethnicity-based differences in the incretin system require further studies. It is now well-established in clinical studies that incretin-related anti-diabetic drugs such as dipeptidyl peptidase-4 inhibitors (DPP-4) and GLP-1 receptor agonists are more effective in Asian people including Japanese with T2D than in Caucasian people with T2D,^39),40) primarily due to their particular pathophysiology. Indeed, DPP-4 inhibitors are the most commonly used first-line therapy for T2D in Japan.⁴¹⁾ Thus, our studies in the past four decades have helped to clarify the physiology and pathophysiology of T2D in East Asian populations and provided important contribution to the current guidelines for its optimal treatment.

Acknowledgements

We thank the members of Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute as well as other collaborators for their contributions.

Notes

Edited by Hiroo IMURA, M.J.A.

Correspondence should be addressed to: Y. Seino, Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, 2-1-7, Fukushima, Fukushima-ku, Osaka 553-0003, Japan (e-mail: [e-mail]).

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Non-standard abbreviation list

BMI

body mass index

DHA

dihydroxyacetone

GIP

glucose-dependent insulinotropic peptide

GK

Goto-Kakizaki

GLP-1

glucagon-like peptide-1

IFG

impaired fasting glucose

IGT

impaired glucose tolerance

IPH

isolated post-challenge hyperglycemia

NGT

normal glucose tolerance

OGTT

oral glucose tolerance test

T2D

type 2 diabetes

US

United States

Profile

Yutaka Seino was born in Fukuoka, Japan on November 7, 1941. Soon after graduation from Kyoto University in 1967, he began his career as a diabetes specialist and committed himself to diabetes care and research. As a diabetes researcher, he found that type 2 diabetes in Asians is characterized by impaired insulin secretion from pancreatic β-cells rather than by insulin resistance as in Caucasians as early as 1975. This finding was at first discounted but is now widely appreciated. He continued his research concentrating especially on the mechanism of insulin secretion from both the clinical and basic points of view. He clarified the mechanism of impaired insulin secretion in type 2 diabetes using the Goto-Kakizaki (GK) rat model, a genetic model of non-obese type 2 diabetes. Furthermore, he contributed significantly to understanding the physiological function of incretin, which greatly helped in the development of incretin-based therapies used worldwide in the management of type 2 diabetes today. During his half-century of dedication to diabetes societies, he has contributed greatly to the improvement of diabetes care and education globally through his tremendous efforts in the International Diabetes Federation (IDF), especially Western Pacific Region (WPR), and the Japan Association of Diabetes Education and Care (JADEC). He also succeeded in establishing the Asian Association for the Study of Diabetes (AASD) and its official journal, the Journal of Diabetes Investigation (JDI), to revitalize diabetes research and care in Asia. Based on these accomplishments, he has received many awards including the International Excellence in Endocrinology Award of the Endocrine Society (USA) in 2014 and the Harold Rifkin Award for Distinguished International Service in the Cause of Diabetes (USA) in 2016.