Leptin and Other Factors as Determinants of Insulin Secretion and Sensitivity in Bangladeshi Type 2 Diabetic Subjects
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Background: The relative contribution of insulin secretion and sensitivity in the development of Type 2 diabetes mellitus (T2DM) vary from population to population due to the heterogeneous nature of the disease. The study was undertaken to evaluate insulin secretory capacity and sensitivity in a Bangladeshi Type 2 diabetic population and to explore the association of some of the anthropometric and biochemical factors known to modulate B-cell function and insulin action. Methods: Ninety one T2DM subjects and 32 age-matched controls were studied for their fasting plasma glucose (FPG), lipids, HbA1c (by HPLC), leptin and C-peptide (ELISA). Insulin secretion (HOMA B) and insulin sensitivity (HOMA S) were calculated by homeostasis model assessment (HOMA). Results: Both insulin secretion and sensitivity were significantly reduced in diabetic as compared to control (HOMA B%, geometric mean±SD, 35.65±1.75 vs. 96.29±1.50, p < 0.001; HOMA S%, 68.66±1.71 vs. 104.951.63, p < 0.001). However, B-cell dysfunction was predominant than insulin resistance in predicting T2DM as the discriminate function coefficient for HOMA B (1.098) was greater than that for HOMA S (0.821). In T2DM, HOMA B had positive correlation with BMI (r=0.368, p < 0.001) and HOMA S was inversely correlated to BMI (r=-0.261, p < 0.01), WHR (r=-0.258, p < 0.01) and plasma TG (r=-0.233, p < 0.001). On multiple regression analysis HOMA B and HOMA S were found to be inversely associated to FPG (p < 0.001) and leptin (p < 0.05) in T2DM. Conclusions: Both insulin secretory dysfunction and insulin resistance are present in Bangladeshi T2DM subjects, but B-cell failure seems to be the predominant abnormality. BMI, plasma glucose, insulin and leptin are the major determinants of insulin secretory capacity and generalized as well as central obesity, plasma glucose, triglycerides, insulin and leptin are among the major determinants of insulin sensitivity in this population. Key Words: Leptin, Insulin, Diabetes  doi: 10.3329/jbsp.v3i0.1786 J Bangladesh Soc Physiol. 2008 Dec;(3):1-7.Keywords:
Homeostasis
In this study, we sought to determine whether insulin resistance, which is investigated by homeostatic modelling, is related to slow coronary flow (SCF).A total of 24 patients with SCF (4 females/20 males, mean age 47 +/- 12 years) and 32 patients with normal coronary artery (10 females/22 males, mean age 52 +/- 12 years) were included in the study. Baseline glucose, insulin and plasma lipid levels were measured. A standard oral glucose tolerance test (OGTT) was performed and post-challenge insulin levels were also measured. The index of insulin resistance was calculated with the homeostatic modelling [homeostatic model assessment for insulin resistance index (HOMA-IR)].There were no differences between the 2 groups with regard to age, lipid levels, blood pressure levels, history of smoking, fasting and post-challenge plasma glucose. Baseline insulin levels were augmented in the SCF group (9.64 +/- 5.93 vs 7.04 +/- 3.26, P = 0.041). HOMA-IR levels were not different between the study groups (2.20 +/- 1.44 vs 1.69 +/- 0.86, P = 0.129). Manifest insulin resistance was significantly higher in the CSF group as compared with the control group (25% vs 3%, P = 0.01).Manifest insulin resistance is seen more frequently in patients with SCF.
Homeostatic model assessment
Homeostasis
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Nonalcoholic fatty liver disease (NAFLD), hepatic insulin resistance, and type 2 diabetes are all strongly associated and are all reaching epidemic proportions. Whether there is a causal link between NAFLD and hepatic insulin resistance is controversial. This review will discuss recent studies in both humans and animal models of NAFLD that have implicated increases in hepatic diacylglycerol (DAG) content leading to activation of novel protein kinase Cϵ (PKCϵ) resulting in decreased insulin signaling in the pathogenesis of NAFLD-associated hepatic insulin resistance and type 2 diabetes. The DAG-PKCϵ hypothesis can explain the occurrence of hepatic insulin resistance observed in most cases of NAFLD associated with obesity, lipodystrophy, and type 2 diabetes.
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목적: 생쥐 실험동물을 이용하여 leptin이 배아발달에 미치는 효과와 각 배아발달 단계에서 leptin 수용체의 발현 양상을 조사하기 위해 수행하였다. 연구 방법: 8~15주령의 C57BL 자성생쥐에 5 IU PMSG와 48시간 후 5 IU hCG를 복강 내 주사한 후, 동종의 웅성생쥐와 1:1 교배시켰다. hCG 주사 후 18시간 후 자성생쥐로부터 1-세포기 배아 (Day 1)를 회수한 다음, 다양한 농도의 생쥐 재조합 leptin (0, 5, 50, 500 ng/mL)을 첨가하면서 포배아까지의 배아발달을 관찰하였다. Leptin이 영향을 미치는 배아발달 단계를 결정하기 위해 동일 농도의 leptin을 2-세포기와 4-세포기 배아시기에 첨가한 후 포배아까지의 배아발달률을 관찰하였다. 포배아에서 세포수를 측정하였으며, 발달 시기별 배아에서 leptin 수용체의 발현을 면역형광법으로 측정하였다. 결과: Leptin이 영향을 미치는 배아발달 단계를 결정하기 위해 동일 농도의 leptin을 2-세포기와 4-세포기 배아시기에 첨가한 후 포배아까지의 배아발달률을 관찰하였다. 포배아에서 세포수를 측정하였으며, 발달 시기별 배아에서 leptin 수용체의 발현을 면역형광법으로 측정하였다. 1-세포기 배아시기에 leptin의 첨가 시 포배아 형성률은 50 ng/mL 농도에서 약 78%로 대조군(53%)에 비해 유의하게 증가한 반면, 500 ng/mL의 고농도에서는 13%로 급격하게 감소하였다 (P<0.05). 2-세포기 배아 단계에 leptin의 첨가는 1-세포기 배아에서의 결과와 비슷한 양상을 보였으나, 4-세포기 배아 단계에서는 leptin의 농도에 따른 배아발달률에 있어서 유의한 차이가 없었다. 또한 1-세포기 배아 단계에서 leptin을 처리했을 때에 비해 leptin 농도에 따른 배아발달향상 효과나 억제 효과가 2-세포기나 4-세포기 배아시기에서 처리 시 다소 둔화된 양상을 보였다. 포배아의 세포수는 1-세포기와 2-세포기 배아시기에서 leptin 처리 후 50 ng/mL 농도에서 대조군에 비해 유의하게 증가한 반면, 500 ng/mL에서는 세포수가 급격하게 감소하였다. 그러나 leptin을 4-세포기 배아시기에 처리시 포배아의 세포수는 leptin 농도에 따른 유의한 차이가 없었다. Leptin 수용체는 1-세포기 배아에서 포배아에 이르는 모든 배아발달 단계에서 발현되었으며, 1-, 2-세포기 배아단계에서 보다 강력한 면역형광반응을 보인 후 배아발달이 진행될수록 감소하다가 포배아기에 다시 증가하는 양상을 보였다. 결론: 생쥐 배아의 체외배양 시 leptin은 농도와 배아발달 시기에 의존적으로 배아발달에 영향을 미치며, 이러한 효과는 각 배아발달 시기의 leptin 수용체 발현 양상과 관계되는 것으로 사료된다.
Leptin receptor
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비만유전자 산물인 leptin은 비만뿐만 아니라 여성의 생식 생리와 관련이 있는 것으로 보이나, 아직 이러한 leptin이 난소에 직접적으로 작용하는지 정확하게 밝혀지지 않고 있다. 따라서 본 연구에서는 흰쥐 난소에서 leptin과 leptin 수용체의 발현을 면역조직화학방법으로 확인하고 발정주기에 따른 leptin과 leptin 수용체의 발현 양상을 RT-PCR 방법으로 조사하고자 하였다. 면역조직화학적 염색방법 결과 흰쥐 난소내에서 leptin은 협막세포와 폐쇄 난포의 일부 과립세포에 염색되었고, leptin 수용체는 협막세포, 간질세포와 난포강이 형성되지 않은 난포의 난자에 염색되었다. 특히 폐쇄 난포에서는 leptin과 leptin 수용체가 정상 난포에 비해 강하게 염색되었다. 흰쥐의 발정주기 동안 혈청내 estradiol, progesterone 및 leptin의 농도는 ELISA 방법으로 측정하였고, 난소내 leptin과 leptin 수용체의 mRNA 발현 양상은 RT-PCR 방법으로 조사하였다. 혈중 leptin 농도를 측정한 결과 estrous 시기에 비하여 metestrous 시기에 유의하게 증가하였고, 이 시기에 progesterone 농도가 함께 증가하는 것을 관찰할 수 있었다. Leptin mRAN는 모든 발정주기에서 발현되지 않았지만 leptin 수용체 mRNA는 diestrous 시기를 제외한 다른 발정주기에 모두 발현되었다. 이러한 결과는 leptin이 흰쥐 난소의 기능을 조절하는데 직접적으로 관여할 수 있다는 것을 제시하고 있다.
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Objective To explore the relationship of serum fasting true insulin (TI) level and insulin resistance (IR) with lipids in patients with type 2 diabetes(T2DM) Methods The fasting TI was determined with BA ELISA method, blood lipids and blood glucose(PG) with an enzyme method in 96 subjects with NC, 132 subjects with T2DM and 148 subjects with T2DM accompanying primary hypertension(T2DM+EH), who did not undergo any antidyslipidemia treatment for a month and antihypertensive treatment for two weeks On the basis of FPG and TI, insulin secretion function (HOMA β) and IR level (HOMA IR) were calculated Results TG and HOMA IR in both T2DM and T2DM+EH groups were significantly higher than those in NC group ( P 0 01) HDL C, HOMA β in T2DM and T2DM+EH groups were significantly lower than those in NC group ( P 0 05) HOMA IR in T2DM+EH group was significantly higher than that in T2DM group HOMA β in T2DM+EH group was higher than that in T2DM group, but the difference was not significant TG had statistically significant positive correlation with TI and HOMA IR( P 0 01), HDL C had statistically negative correlation with TI and HOMA IR ( P 0 05) in both T2DM and T2DM+EH Conclusion Serum true insulin level and insulin resistance are associated with dyslipidemia in type 2 diabetes The elevated true insulin and/or serious insulin resistance will elevate TG and decrease HDL C Insulin resistance is more associated with dyslipidemia than truly hyperinsulinemia
Dyslipidemia
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Lipid Profile
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비만유전자 산물인 leptin은 지방 조직에서 생성되어 혈액으로 분비되며,신진대사,식욕,체열 등을 조절하여 비만의 억제 조절 물질로 작용하는 것으로 알려져 있다. 또한 leptin은 비만 뿐만 아니라 생식 생리와도 관련이 있는 것으로 보이며, 이러한 leptin의작용이 난소에 직접적인지 혹은 시상하부나 뇌하수체를 매개로 하는지는 아직 정확하게 밝혀지지 않고 있으며, 난소에서의 Ieptin 및leptin 수용체의 발현 양상에 대한 연구 또한 미진한 상태에 있다. 따라서 본 연구는 생후 3주령과 8주령의 횐쥐 난소에서 leptin과leptin 수용체의 발현 양상을 면역조직화학방법과 RT-PCR 방법으로 조사하였다. 면역조직화학방댑 결과 3주령과 8주령 횐쥐 모두에서 leptin은 협막세포와 폐쇄 난포의 일부 과립세포에 염색되었고, leptin수용체는 협막세포,간질세포와 난포강이 형성되지 않은 난포의 난자에 염색되었다. RT-PCR견과 3주 및 8주 횐쥐 난소에서 leptin mRNA는 모두 발현되지 않은 반면, Ieptin수용체 mRNA는 모두 발현되었다. 결론적으로 leptin mRNA가 난소에서 발현되지는 않지만, 면역조직화학방법으로 leptin의 발현을 확인하였고, leptin수용체는 난소에서 RT-PCR 방법과 면역조직화차방법으로 모두 확인할 수 있었다. 이러한 결과로 보아 혈액에서 난소 내로 유입된leptin이 협 막세포, 간질세포와 난자의 leptin 수용체 에 결합하여 난소의 생리적 기능을 조절할 수 있는 것으로 사료된다.
Leptin receptor
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AbstractMany studies have reported the difficulty most subjects have in maintaining weight loss. Leptin is a cytokine-like protein made in adipose tissue and is transported into the brain by the blood–brain barrier where it inhibits food intake by altering the expression of hypothalamic neurotransmitters. The discovery of leptin raised the hope that a natural compound had been found that could cause weight loss without adverse effects. However, the majority of obese people have high levels of circulating leptin and it is not surprising that clinical trials published so far have shown that leptin only works effectively to suppress food intake in subjects who are hyperphagic as a result of low leptin levels. Obesity secondary to leptin deficiency is rare, most being associated with leptin insensitivity. To overcome leptin insensitivity, higher leptin levels in the CNS may be required. However, there is evidence that the leptin transport mechanism is saturated at low plasma leptin concentrations, limiting the effectiveness of peripherally-administered hormone. It is concluded that for leptin to have therapeutic potential, it either needs to be modified or the transport system by which leptin enters the brain needs to be upregulated to allow leptin to enter the brain more easily. To achieve effective weight loss, it may also be necessary to overcome central leptin insensitivity by developing agents that act downstream of leptin action.Keywordsbloodbrain barrierobesityweight loss
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Many studies have reported the difficulty most subjects have in maintaining weight loss. Leptin is a cytokine-like protein made in adipose tissue and is transported into the brain by the blood–brain barrier where it inhibits food intake by altering the expression of hypothalamic neurotransmitters. The discovery of leptin raised the hope that a natural compound had been found that could cause weight loss without adverse effects. However, the majority of obese people have high levels of circulating leptin and it is not surprising that clinical trials published so far have shown that leptin only works effectively to suppress food intake in subjects who are hyperphagic as a result of low leptin levels. Obesity secondary to leptin deficiency is rare, most being associated with leptin insensitivity. To overcome leptin insensitivity, higher leptin levels in the CNS may be required. However, there is evidence that the leptin transport mechanism is saturated at low plasma leptin concentrations, limiting the effectiveness of peripherally-administered hormone. It is concluded that for leptin to have therapeutic potential, it either needs to be modified or the transport system by which leptin enters the brain needs to be upregulated to allow leptin to enter the brain more easily. To achieve effective weight loss, it may also be necessary to overcome central leptin insensitivity by developing agents that act downstream of leptin action.
Limiting
Leptin receptor
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We thank Prof. Dogru and colleagues for their interest in our recent article on the importance of adipocyte fatty acid binding protein (AFABP) in nonalcoholic fatty liver disease (NAFLD).1 It is now well accepted that NAFLD is the hepatic manifestation of the metabolic syndrome and as such is intimately associated with insulin resistance, visceral obesity, and dyslipidemia.2 Insulin resistance, which is a key characteristic of both conditions, has also been associated with NAFLD progression from simple steatosis to nonalcoholic steatohepatitis.3 We used the homeostasis model assessment of insulin resistance (HOMA-IR) to reflect the spectrum of insulin sensitivity. This index has been shown to correlate with the results of euglycemic-hyperinsulinemic clamp in patients without diabetes and with type 2 diabetes, including those treated with metformin and other oral hypoglycemic agents.4, 5 We were careful to exclude those taking thiazolidenediones, which have been shown to significantly affect circulating adipokine levels,6, 7 in contrast to sulfonylureas and metformin, which have not.7, 8 Type 2 diabetes eventually ensues in many subjects with increasing insulin resistance and is associated with more progressive fatty liver disease9; therefore, we decided not to exclude subjects with type 2 diabetes in our study. Although we agree it would be interesting to further subclassify subjects by glucose dysregulation status, the use of post hoc subset analysis is far less robust statistically and prone to type 2 error. We agree that metabolic variables and, in particular, measures of insulin resistance are important to consider when interpreting data on adipocytokines, which are intimately related to these factors. Indeed, our data showed the close association between both AFABP and lipocalin-2 to insulin resistance, body mass index, and waist circumference. To ensure our findings were independent of key confounders, we performed multivariate analysis for each histological endpoint in NAFLD using those factors significant on univariate analysis.1 We demonstrated that the association between AFABP and necroinflammatory and fibrotic activity is independent of abdominal obesity (the waist-hip ratio), cholesterol, high-density lipoprotein, and insulin resistance. For further clarity, as suggested by Prof. Dogru, we provide in Table 1 the relationship between AFABP and disease severity in NAFLD, directly controlled for insulin resistance and the key metabolic variables of body mass index, low-density lipoprotein, high-density lipoprotein, triglycerides, and glucose. This conclusively demonstrates that AFABP plays an important role in the pathogenesis of NAFLD independent of metabolic confounders. David van der Poorten*, Kerry-Lee Milner , Donald J. Chisholm , Jacob George*, * Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, Australia, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia.
Dyslipidemia
Steatohepatitis
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客观肥胖荷尔蒙， leptin，被发现了参予正常、恶意的纸巾的发展和增长。这研究的目的是在人的颜色评估 leptin 的角色表面的癌症。方法浆液 leptin 层次在 30 颜色经由 ABC-ELLSA 被测量表面的癌症和 24 正常控制。在颜色的 Leptin 集中表面的癌症以选择 clinicopathological 特征和某 oncogenes 被分析。结果 leptin 的吝啬的集中是显著地更高的为比正常控制(2.27 ± 0 .99 ng/ml ) 渲染表面的癌症(3.54 ± 1 .46 ng/ml ) ，没有性差别在这研究被观察。在糟糕区分的肿瘤的 Leptin 表示显然是比在中等并且很好区分的肿瘤的那些低的。在颜色在 leptin 和浆液 CEA 和 CA199 之间没有统计上重要的关联表面的癌症(P>0.05 ) ，并且在 leptin 和 K 地岬的表情之间， P53， APC，在肿瘤纸巾(P>0.05 ) 的两重棉包线基因。结论 Leptin 完了在人的颜色表示了表面的癌症，它与肿瘤的区别度有关。在 leptin 表示和在颜色的 oncogenes 的变化之间没有关联表面的癌症。
Leptin receptor
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