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Impaired suppression of endogenous glucose production in lean Japanese patients with type 2 diabetes mellitus
diabetes research and clinical practice 93 (2011) e1–e2
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Letter to the Editor Impaired suppression of endogenous glucose production in lean Japanese patients with type 2 diabetes mellitus The number of type 2 diabetic patients has rapidly increased in Asia and it is of note that a substantial part of them are free of obesity, unlike Caucasian patients [1–3]. It is essential in management of this diabetes epidemic in Asia to reveal the underlying pathogenesis of lean Asian patients with type 2 diabetes. The pathophysiological influence of their genetic predisposition toward impaired insulin secretion has often been highlighted but their insulin sensitivity, especially endogenous glucose production (EGP) and peripheral glucose uptake (PGU), remains so far to be investigated in detail. We measured EGP and PGU with 6,6-[2H]glucose in 32 Japanese type 2 diabetic patients who were lean (BMI < 25, n = 11), overweight (25 BMI < 30, n = 12) and obese (BMI 30, n = 9). EGP was positively correlated with fasting plasma glucose (FPG) (r = 0.499, p = 0.004), whereas PGU was negatively correlated with FPG (r = 0.567, p = 0.001). We subsequently examined the difference of EGP and PGU among the groups (Table 1). Interestingly, diabetic patients with lower BMI had higher EGP ( p = 0.001), as well as higher PGU ( p = 0.018), while there was no association between BMI and FPG ( p = 0.665). Furthermore, both EGP and PGU were significantly correlated
with BMI independently of FPG; their partial correlation coefficients were 0.693 ( p < 0.001) and 0.727 ( p < 0.001), respectively. Plasma insulin concentration was lower in patients with lower BMI ( p = 0.002), and it was significantly correlated with EGP (r = 0.449, p = 0.010) but not PGU (r = 0.146, p = 0.426). We revealed that EGP was elevated in lean Japanese patients compared with obese patients, which was different from previous Caucasian observations [4,5]. They reported that obese patients had higher EGP and concluded that obesity had additive effects on hepatic insulin resistance of type 2 diabetes. Our current study found that this did not seem true of Japanese diabetic patients. Increased EGP is often expressed as hepatic insulin resistance and the impaired suppression of EGP in lean patients rather than obese patients is seemingly paradoxical. It is also known, however, that insufficient insulin fails to suppress EGP. Our patients with lower BMI had lower plasma insulin concentrations and one possible explanation of this apparent paradox is that their impaired suppression of EGP reflected their insufficient insulin secretion. In conclusion, suppression of EGP was markedly impaired in lean Japanese patients compared with obese patients, which could hardly be expected from the previous studies of diabetic Caucasians [4,5]. One should consider this paradoxical characteristic in management of Japanese patients with type 2 diabetes.
Conflict of interest Table 1 – Metabolic characteristics of lean, overweight and obese patients with type 2 diabetes mellitus. Lean Overweight p Obese group group value* group (BMI < 25) (25 BMI (BMI 30) < 30) BMI (kg/m2) EGP (mmol/kg/min) PGU (ml/kg/min) FPG (mmol/l) Insulin (pmol/l)
21.9 3.0 13.8 1.8
28.6 1.2 11.3 2.1
33.3 3.0 10.4 2.0
<0.001 0.001
2.3 0.6 6.5 1.6 32 17
2.0 0.4 5.9 1.1 51 29
1.8 0.3 6.2 1.7 144 132
0.018 0.665 0.002
Data are mean SD. p value: test for a linear trend in one-way ANOVA. BMI, body mass index; EGP, endogenous glucose production; PGU, peripheral glucose uptake; FPG, fasting plasma glucose. *
There are no conflicts of interest.
references
[1] Ramachandran A, Ma RC, Snehalatha C. Diabetes in Asia. Lancet 2010;375:408–18. [2] Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet 2006;368:1681–8. [3] Sone H, Ito H, Ohashi Y, Akanuma Y, Yamada N. Obesity and type 2 diabetes in Japanese patients. Lancet 2003;361:85. [4] Perriello G, Misericordia P, Volpi E, Pampanelli S, Santeusanio F, Brunetti P, et al. Contribution of obesity to insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1995;80:2469–79.
e2
diabetes research and clinical practice 93 (2011) e1–e2
[5] Gastaldelli A, Miyazaki Y, Pettiti M, Buzzigoli E, Mahankali S, Ferrannini E, et al. Seperate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis. J Clin Endocrinol Metab 2004;89:3914–21.
Mitsuyoshi Takahara Hideaki Kaneto* Naoto Katakami Taka-aki Matsuoka Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan Munehide Matsuhisa Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan
Iichiro Shimomura Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan *Corresponding author. Tel.: +81 6 6879 3743; fax: +81 6 6879 3739 E-mail address: [email protected] ( H. Kaneto) 27 December 2010
0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.03.002
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Letter to the Editor Impaired suppression of endogenous glucose production in lean Japanese patients with type 2 diabetes mellitus The number of type 2 diabetic patients has rapidly increased in Asia and it is of note that a substantial part of them are free of obesity, unlike Caucasian patients [1–3]. It is essential in management of this diabetes epidemic in Asia to reveal the underlying pathogenesis of lean Asian patients with type 2 diabetes. The pathophysiological influence of their genetic predisposition toward impaired insulin secretion has often been highlighted but their insulin sensitivity, especially endogenous glucose production (EGP) and peripheral glucose uptake (PGU), remains so far to be investigated in detail. We measured EGP and PGU with 6,6-[2H]glucose in 32 Japanese type 2 diabetic patients who were lean (BMI < 25, n = 11), overweight (25 BMI < 30, n = 12) and obese (BMI 30, n = 9). EGP was positively correlated with fasting plasma glucose (FPG) (r = 0.499, p = 0.004), whereas PGU was negatively correlated with FPG (r = 0.567, p = 0.001). We subsequently examined the difference of EGP and PGU among the groups (Table 1). Interestingly, diabetic patients with lower BMI had higher EGP ( p = 0.001), as well as higher PGU ( p = 0.018), while there was no association between BMI and FPG ( p = 0.665). Furthermore, both EGP and PGU were significantly correlated
with BMI independently of FPG; their partial correlation coefficients were 0.693 ( p < 0.001) and 0.727 ( p < 0.001), respectively. Plasma insulin concentration was lower in patients with lower BMI ( p = 0.002), and it was significantly correlated with EGP (r = 0.449, p = 0.010) but not PGU (r = 0.146, p = 0.426). We revealed that EGP was elevated in lean Japanese patients compared with obese patients, which was different from previous Caucasian observations [4,5]. They reported that obese patients had higher EGP and concluded that obesity had additive effects on hepatic insulin resistance of type 2 diabetes. Our current study found that this did not seem true of Japanese diabetic patients. Increased EGP is often expressed as hepatic insulin resistance and the impaired suppression of EGP in lean patients rather than obese patients is seemingly paradoxical. It is also known, however, that insufficient insulin fails to suppress EGP. Our patients with lower BMI had lower plasma insulin concentrations and one possible explanation of this apparent paradox is that their impaired suppression of EGP reflected their insufficient insulin secretion. In conclusion, suppression of EGP was markedly impaired in lean Japanese patients compared with obese patients, which could hardly be expected from the previous studies of diabetic Caucasians [4,5]. One should consider this paradoxical characteristic in management of Japanese patients with type 2 diabetes.
Conflict of interest Table 1 – Metabolic characteristics of lean, overweight and obese patients with type 2 diabetes mellitus. Lean Overweight p Obese group group value* group (BMI < 25) (25 BMI (BMI 30) < 30) BMI (kg/m2) EGP (mmol/kg/min) PGU (ml/kg/min) FPG (mmol/l) Insulin (pmol/l)
21.9 3.0 13.8 1.8
28.6 1.2 11.3 2.1
33.3 3.0 10.4 2.0
<0.001 0.001
2.3 0.6 6.5 1.6 32 17
2.0 0.4 5.9 1.1 51 29
1.8 0.3 6.2 1.7 144 132
0.018 0.665 0.002
Data are mean SD. p value: test for a linear trend in one-way ANOVA. BMI, body mass index; EGP, endogenous glucose production; PGU, peripheral glucose uptake; FPG, fasting plasma glucose. *
There are no conflicts of interest.
references
[1] Ramachandran A, Ma RC, Snehalatha C. Diabetes in Asia. Lancet 2010;375:408–18. [2] Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet 2006;368:1681–8. [3] Sone H, Ito H, Ohashi Y, Akanuma Y, Yamada N. Obesity and type 2 diabetes in Japanese patients. Lancet 2003;361:85. [4] Perriello G, Misericordia P, Volpi E, Pampanelli S, Santeusanio F, Brunetti P, et al. Contribution of obesity to insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1995;80:2469–79.
e2
diabetes research and clinical practice 93 (2011) e1–e2
[5] Gastaldelli A, Miyazaki Y, Pettiti M, Buzzigoli E, Mahankali S, Ferrannini E, et al. Seperate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis. J Clin Endocrinol Metab 2004;89:3914–21.
Mitsuyoshi Takahara Hideaki Kaneto* Naoto Katakami Taka-aki Matsuoka Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan Munehide Matsuhisa Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan
Iichiro Shimomura Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan *Corresponding author. Tel.: +81 6 6879 3743; fax: +81 6 6879 3739 E-mail address: [email protected] ( H. Kaneto) 27 December 2010
0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.03.002