Role of insulin-like growth factor binding protein-3 in glucose and lipid metabolism

김호성 대한소아내분비학회 2013 Annals of Pediatirc Endocrinology & Metabolism Vol.18 No.1

Insulin-like growth factor binding protein (IGFBP)-3 has roles in modulating the effect of IGFs by binding to IGFs and inhibiting cell proliferation in an IGF-independent manner. Although recent studies have been reported that IGFBP-3 has also roles in metabolic regulation, their exact roles in adipose tissue are poorly understood. In this review, we summarized the studies about the biological roles in glucose and lipid metabolism. IGFBP-3 overexpression in transgenic mice suggested that IGFBP-3 results in glucose intolerance, and insulin resistance. IGFBP-3 knockout (KO) mice exhibited normal insulin level and glucose response after glucose challenge. More recent study in IGFBP-3 KO mice with a high-fat diet demonstrated that IGFBP-3 KO mice exhibited elevated fasting glucose and insulin, but normal response to glucose challenge, suggesting that IGFBP-3KO mice may induce insulin resistance even though preserved insulin sensitivity. In vitro and in vivo studies using 3T3-L1 adipocytes and rat, IGFBP-3 induced insulin resistance by inhibiting glucose uptake. In contrast, the reduced levels of IGFBP-3 in obesity might induce insulin resistance by suppression of IGFBP-3’s anti-inflammatory function,suggesting IGFBP-3 has a protective effect on insulin resistance. Also, proteolysis of IGFBP-3 might contribute to the insulin resistance in obesity and type 2 diabetes mellitus. In addition, IGFBP-3 inhibited adipocyte differentiation, suggesting IGFBP-3 may contribute to the insulin insensitivity. Taken together, it is not yet certain that IGFBP-3 has a protective effect or enhancing effect on insulin resistance, and more studies will be needed to clarify the roles of IGFBP-3 in metabolic regulation.

Use of insulin detemir in dogs with diabetes mellitus

Hyo-Mi Jang,Na-Young Eom,Yang-Ho Kang,Dong-In Jung 충북대학교 동물의학연구소 2015 Journal of Biomedical and Translational Research Vol.16 No.1

Insulin detemir is a long-acting basal insulin analogue recently introduced in veterinary medicine for treatment of canine diabetes mellitus. As there are only limited studies in dogs, long-term evaluation of insulin detemir in veterinary medicine is required. In this study, we investigated trends in12-hour blood glucose concentration during hospitalization and evaluated initial and following doses of insulin detemir for several months in six diabetic dogs. The mean levels of blood glucose over 12-hour periods were between 113.5 to 327.2 mg/dL, and the average glucose nadir was 103 mg/dL in the six dogs. The dogs were treated with a mean dosage of 0.24 U/kg of insulin detemir, but hypoglycemia was observed in four of the dogs at the first monthly follow-up. Thus, insulin doses were adjusted according to the nadir levels of glucose observed during the follow-up periods (range, 1 to 16 months). The total range of insulin doses throughout the study period was between 0.1 and 0.4 U/kg. Changes in insulin doses in each dog during the follow-up period were not variable. We suggest that insulin detemir might be not only an alternative choice against traditional insulin for patients with insulin resistance or concurrent disease but also an effective home therapy medication in canine patients with DM. This study could help inform veterinary practitioners regarding the use of insulin detemir for canine insulin-dependent DM.

Visceral obesity is a better predictor than generalized obesity for basal insulin requirement at the initiation of insulin therapy in patients with type 2 diabetes

Kim, Mee Kyoung,Jang, Eun Hee,Son, Jang Won,Kwon, Hyuk-Sang,Baek, Ki-Hyun,Lee, Kwang-Woo,Song, Ki-Ho Elsevier 2011 Diabetes research and clinical practice Vol.93 No.2

<P><B>Abstract</B></P> <P><B>Aims</B></P> <P>Basal insulin requirement in patients with type 2 diabetes is difficult to determine because of individual variability in insulin sensitivity and secretion. We aimed to identify factors that influence basal insulin requirement in insulin-naïve patients with type 2 diabetes.</P> <P><B>Methods</B></P> <P>We studied 50 insulin-naïve patients with type 2 diabetes. Their basal insulin requirement was calculated by 8h overnight intravenous insulin infusion. Patients underwent abdominal computed tomography; subcutaneous and visceral fat areas were measured.</P> <P><B>Results</B></P> <P>The basal insulin requirement was 31.3±16.9units/day, and it varied widely from 0.2 to 1.4units/kg. It was positively correlated with visceral fat area (<I>γ</I> =0.485, <I>P</I> <0.001), body mass index (BMI, <I>γ</I> =0.339, <I>P</I> =0.008), glycated hemoglobin (HbA1C, <I>γ</I> =0.327, <I>P</I> =0.019), alanine aminotransferase (ALT, <I>γ</I> =0.310, <I>P</I> =0.027), and triglyceride (<I>γ</I> =0.305, <I>P</I> =0.032). However, body weight, waist circumference and total fat mass were not related to basal insulin requirement. Multiple linear regression analysis showed that visceral fat area, HbA1C, and ALT are independent predictors of basal insulin requirement.</P> <P><B>Conclusions</B></P> <P>Visceral obesity was a better predictor than generalized obesity for basal insulin requirement at the initiation of insulin therapy in patients with type 2 diabetes.</P>

Review : Molecular Mechanism of Insulin Resistance in Obesity and Type 2 Diabetes

( Kang Duk Choi ),( Young Bum Kim ) 대한내과학회 2010 The Korean Journal of Internal Medicine Vol.25 No.2

Insulin resistance is a major risk factor for developing type 2 diabetes caused by the inability of insulin-target tissues to respond properly to insulin, and contributes to the morbidity of obesity. Insulin action involves a series of signaling cascades initiated by insulin binding to its receptor, eliciting receptor autophosphorylation and activation of the receptor tyrosine kinase, resulting in tyrosine phosphorylation of insulin receptor substrates (IRSs). Phosphorylation of IRSs leads to activation of phosphatidylinositol 3-kinase (PI3K) and, subsequently, to activation of Akt and its downstream mediator AS160, all of which are important steps for stimulating glucose transport induced by insulin. Although the mechanisms underlying insulin resistance are not completely understood in skeletal muscle, it is thought to result, at least in part, from impaired insulin-dependent PI3K activation and downstream signaling. This review focuses on the molecular basis of skeletal muscle insulin resistance in obesity and type 2 diabetes. In addition, the effects of insulin-sensitizing agent treatment and lifestyle intervention of human insulin-resistant subjects on insulin signaling cascade are discussed. Furthermore, the role of Rho-kinase, a newly identified regulator of insulin action in insulin control of metabolism, is addressed. (Korean J Intern Med 2010;25:119-129)

인슐린 농도 변화에 따른 인슐린 내재화 ( Internalization ) 와 Degradation 의 변화

박원근(Won Kun Park),최웅환(Woong Hwan Choi),한인권(In Kwon Han),김선우(Sun Woo Kim),정운원(Woon Won Jung),문인걸(In Gul Moon) 대한내과학회 1988 대한내과학회지 Vol.34 No.4

N/A This study was conducted to investigate the effect of ambient concentration of insulin on insulin internalization and degradation in human erythrocytes. The absolute amount of internalized insulin was quantitated by multiplying the concentration of insulin by the percent specifically bound and internalized (by acid extraction method, PBS, pH 5.7) at the various insulin concentration (1.4, 2.5, 12.4, 112.4 ng/m1). The insulin degradation products (IDP) was assayed by using Sephadex G-50 column, HPLC with radioisotope detector in human erythrocytes which were incubated (37℃) at the various insulin concentration (1.43, 2.76, 14.76, 26.60ng/ml). Insulin internalization (ng/ml) increased in human erythrocytes with increasing concentration of insulin (3hr incubation time, 0.336 at 1.4, 0.275, at 2,5, 3.844 at 12.4, and 24.728ng/ml at 112.4ng/ml, 4hr incubation time, 0. 476, at 1.4, 0.925 at 2.5, 4.712 at 12.4 and 38.216ng/ml at 112.4ng/ml). Insulin degradation products (%) increased (2hr incubation time, 20.9 at 1,43; 38.0 at 2.76 and 38.0% at 14.76ng/ml) but no more than at a level of insulin concentration (2.76ng/ml) in normal human erythrocytes. In diabetic human erythrocytes, insulin degradation products (%) also increased (3br incubation time, 14.1 at 1.43, 19.0 at 2,76, 23.0 at 14.76, and 23.2% at 26.60ng/ml, 4hr incubation time, 39.4 at 1.43, 46.9 at ~2.76, 52. S at 14.76 and 53.0% at 26.60ng/ml) but no more than at a level of insulin concentration (14.76ng/ml), This result indicated that the ambient concentration of insulin may play an important role in the regulation of intracellular processing of insulin.

임신 후반기 흰쥐의 인슐린 저항성과 그 기전

이석강,전명흡,김용운,박소영,김종연 영남대학교 의과대학 1995 Yeungnam University Journal of Medicine Vol.12 No.2

임신시 발생하는 인슐린 저항성과 인슐린 분비 증가의 기전을 규명하기 위하여 Sprague-Dawley 종 암컷 흰쥐를 이용하여 정맥당부하 검사와 호르몬 및 지방 대사물질과 조직에서의 인슐린 수용체 결합, 당원질 합성효소를 분석한 결과를 요약하면 다음과 같다. 정맥당부하검사에서 임신군에서 전체적인 곡선이 대조군에 비하여 아래에 위치하였다. 그러나 당부하시 인슐린 분비는 현저히 증가하였으며 혈당에 대한 비(μU/mg)로 비교하여 임신군에서 56.9±8.9였고 대조군에서 23.6±2.8로서 인슐린 저항성을 확인할 수 있었다. 인슐린 분비반응의 증가는 태반 호르몬인 Progesterone의 증가와 강한 상관관게를 나타내었다. 당부하검사후 당원질(mg/100mg tissue)은 골격근(soleus)에서는 임신군과 대조군간에 유의한 차이가 없었으나 간조직에서는 임신군에서 4.7±0.9으로 대조군의 9.9±1.3에 비하여 통계적으로 유의하게 감소하였다. 당원질로 합성된 ??-glucose의 활동도도 마찬가지로 골격근에서는 임신군과 대조군간에 유의한 차이가 없었으나 간조직에서는 현저한 감소를 보였다. 당원질합성효소(glycogen synthase)는 골격근에선는 대조군이 높았고 간장조직에서는 임신군이 높았으나 유의한 차이는 없었다. 당부하검사후 간장조직의 crude membrane에 서의 인슐린-인슐린 수용체 결합반응에서는 두군 사이에 유의한 차이가 없었다. 이상의 결과로 보아 정상임신흰쥐에서 인슐린 저항성이 발생하였으나 인슐린 분비의 현저한 증가로 내당능의 감소는 나타나지 않았으며 인슐린의 분비증가는 progesterone의 증가와 상관관계가 있었다. 인슐린 저항성은 간에서 가장 현저하게 나타났으며 그 원인은 인슐린 수용체의 결합과정보다는 수용체 전 과정이거나 수용체 후 과정일 것으로 추정된다. The influence of normal late pregnancy on insulin action and insulin secretion was studied in the Sprague-Dawley female rats. On 20th day after mating, intravenous glucose tolerance test(IVGTT) was performed in non pregnant control and pregnant rats. As results of IVGTT, glucose disappearance rate was not significantly different in both groups, but secretory response of insulin was significantly (p<0.05) increased in pregnant rat. And the ratio of insulin/glucose was significantly higher in pregnant rats, which means existence of insulin resistance. These insulin resistance was overcomed by increased secretory response of pancreatic insulin. Insulinogenic index(△insulin/glucose - 5 min) was higly significantly (r=0.62, P<0.01) correlated with progesterone concentration. Glycogen level and amounts of ??-glucose incorporated into glycogen after IVGTT were significantly(p<0.05) decreased in the liver, but were not changedsignificantly in soleus. Glycogen synthase activity of soleus and liver was not differ significantly in the both groups. Insulin binding at varying concentrations of insulin to crude membrane of pregnant live was not significantly different from control. In conclusions, although these pregnant rats were normal glucose tolerance due to increased secretory response of insulin, that was correlated with progesterone concentration, pregnant rat had insulin resistance. The mechanisms of insulin resistance were not related to defect of insulin binding phase and glycogen synthase, but suggest pre-receptor and/or postreceptor phase.

Insulin Binding and its Action in Adipocytes of Hyperthyroid and Hypothyroid Rats

Kang, Sung Ku,Cha, Bong Yun,Kim, Young Woo,Bang, Byong Kee,Min, Byong Sok,Son, Ho Young,Lee, Kwang Woo,Kim, Hak Joong CATHOLIC MEDICAL CENTER 1986 Bulletin of the Clinical Research Institute Vol.14 No.1

The studies of the effects of thyroid hormone on insulin secretion and glucose metabolism have been made, but the results have been controversial. In order to evaluate the effects of thyroid hormone at the cellular level, insulin binding and insulin-induced lipogenesis in isolated rat epididymal fat cells were studied in control, hyperthyroid and hypothyroid rats. Hyperthyoidism was induced by daily intraperitoneal injection of sodium L-thyroxine and hypothyroidism by a single injection of ^131I. The adipocytes were isolated by treatment of collagenase as originally described by Gliemann (1967). The results were as follows: 1. The fasting serum insulin levels of hyperthyroid (21.6±3.7 uU/ml) and hypothyroid groups (20.5 ± 7.0 uU/ml) were not different from the value of control (23.1 ± 11 uU/ml). The fasting blood glucose level of hypothyroid group (164.9 ± 12.0 mg/dl) was higher than the values of the controls (148.2±13.2 mg/dl) or the hyperthyroid group (147.0±12.5 mg/dl), (p < .005). 2. The specific ^125l-insulin binding of the hyperthyroid group was not different from the value of the controls, but the value of the hypothyroid group was higher than the value of the controls (p<.005). 3. The insulin receptor concentration of the hypothyroid group (1.09±0.02ng/0.5×10exp(5) cells) was higher than the value of the controls (0.72±0.01ng/0.5×10exp(5) cells) or the hyperthyroid roup (0.79±0.02ng/0.5×10s cells), (p<.05). 4. The average affinities of the receptors in all groups showed an inverse correlation with the insulin concentration. The average affinity of the hypothyroid group was higher than the value of the control or the hyperthyroid group. 5. Insulin-induced lipogenesis was reduced proportionately in all insulin concentrations in both the hyperthyroid and hypothyroid groups compared with the dose-response curve of the control group. The maximal amount of Ilipogenesis of the hyperthyroid and hypothyroid groups were 63.4% (p<.05) and 32.3% (p<.005) of the controls, respectively. These studies suggest that thyroid hormone may regulate the concentration of insulin receptors, and altered thyroid states reduce insulin-induced lipogenesis in the adipocyte at post-receptor levels.

생쥐 초기배아에서 Insulin과 Tumor Necrosis Factor $\alpha$에 의한 발생의 조절

계명찬,한현주,최진국 한국발생생물학회 2001 발생과 생식 Vol.5 No.2

Present study was aimed to verify the role of insulin and TNF-$\alpha$ in development of preimplantation embryos. Mouse morula were cultured for 40 hr in the presence or absence of insulin(400 ng/ml) and TNF-$\alpha$ (50 ng/ml). The morphological development, cell number of blastomeres per blastocyst, and mitogen activated protein kinase(MAPK) activity were examined. The developmental rate and cell number per embryo were the highest in insulin treatment group and the lowest in TNF-$\alpha$ treatment group. There was no significant difference in developmental rate between control and insulin plus TNF-$\alpha$ group. Taken together, it suggested that TNF-$\alpha$ impaired embryonic development and that insulin rescued developmental impairment imposed by TNF-$\alpha$. In blastocysts, insulin treatment significantly increased MAPK activity. TNF-$\alpha$ decreased the MAPK activity in a concentration-dependent manner. In the TNF-$\alpha$(50 ng/ml) -primed embryos, activation of MAPK by insulin was attenuated. In conclusion, these results suggest that there was a cross talk between insulin and TNF-$\alpha$ by means of activation of MAPK in preimplantation embryos and that insulin might rescue damage of embryos exposed to TNF-$\alpha$. Insulin과 tumor necrosis factor alpha(TNF-$\alpha$)에 의한 초기 배아 발생의 조절기작을 알아보고자 생쥐의 상실배를 대상으로 이들이 첨가된 배양액에서 형태발생, 세포증식을 조사하고, 포배에서 mitogen activated protein kinase(MAPK, ERK1/2)의 활성 변화에 미치는 영향을 조사하였다. Insulin은 상실배의 체외발생 및 포배내 할구 수를 대조군에 비해 유의하게 증가시켰으며, TNF-$\alpha$는 발생율을 유의하게 감소시켰다. Insulin은 TNF- $\alpha$에 의한 배아 발생율 감소를 완화하였다. TNF-$\alpha$는 농도에 의존적으로 MAPK 활성을 감소시켰으며, insulin은 포배에서 MAPK의 활성을 유의하게 증가시킨 반면 TNF-$\alpha$는 처리농도에 의존적으로 MAPK 활성을 감소시켰다. 50 ng/ml 농도의 TNF-$\alpha$를 전처리한 포배에서는 insulin에 의한 MAPK 활성의 증가가 저해되었다. 이러한 결과로부터 생쥐의 착상전 초기 배아 발생조절에 insulin과 TNF-$\alpha$ 사이에 MAPK를 경유하는 cross talk이 존재함을 확인하였고 insulin은 TNF-$\alpha$ 에 의한 배아의 손상을 억제하는 것으로 사료된다.

Insulin 측정용 방사면역측정법 시약의 평가

신용환,김윤현,이일규,김지영,석재동,신숙희,Shin, Yong Hwan,Kim, Yun Hyun,Lee, Il Kyu,Kim, Ji Young,Seok, Jae Dong,Shin, Suk Hee 대한핵의학기술학회 2012 핵의학 기술 Vol.16 No.2

혈중 Insulin 농도는 췌장 ${\beta}$세포의 인슐린 분비기능을 반영하고 당뇨병의 진단, 병태 파악, 내당능 이상의 원인감별에 유용한 지표이다. 핵의학검사실에서 사용하고 있는 혈중 Insulin 측정용 시약들은 제조회사마다 검사방법 뿐만 아니라 비용효과 측면, 정밀도 등 정도관리 측면에서도 다소 차이를 보이고 있다. 따라서 Insulin 측정용 방사면역측정법 시약들의 제조 회사별 비교를 통해 진단적 성능을 평가하고자 본 연구를 시행하였다. 2009년 8월 59명의 환자 검체를 대상으로 시행된 3개 제조회사(Biosource, Siemens, TFB)의 혈중 Insulin측정치와 2011년 12월 68명의 환자 검체를 대상으로 시행된 4개 제조회사(Immunotech, Izotope, BNIBT, Cisbio)의 혈중 Insulin측정치를 비교 평가하였다. 이들 7개 제조회사별 Insulin측정치에 대하여 정밀도, 회수율, 상관관계를 살펴보았으며 일부 인슐린 고농도 특이검체를 가지고 희석시험을 통해 혈중 Insulin측정치를 상호 비교 평가하였다. 혈중 Insulin 측정은 시약 내 설명서의 권고사항을 준수하여 실시하였으며 결과 검증을 위한 통계 프로그램은 SPSS 12.0을 이용하였다. 측정 내 정밀도는 Biosource, Siemens, TFB, Immunotech, Izotope, BNIBT, Cisbio 7개 제조회사 모두 5.0% 이하의 변이계수를 보였다. 회수율은 저, 중, 고 세가지 농도의 혈청에서 Biosource, Siemens, TFB시약이 각각 94.2~103.7%, 99.0~104.6%, 99.7~107.6% 구간을 보였고 Immunotech, Izotope, BNIBT, Cisbio 시약에서 각각 93.5~99.1%, 91.4~99.1%, 99.2~131.0%, 84.8~102.3% 구간의 회수율을 보였다. Biosource 시약을 기준으로 비교한 상관관계에서 Siemens 시약이 R2=0.96(P<0.01), TFB시약이 R2=0.99(P<0.01)를 보였으며 TFB 시약을 기준으로 비교한 상관관계에서는 BNIBT시약(R2=0.80, P<0.01)을 제외한 대부분의 시약에서 강한 상관관계(R2=0.96 이상, p<0.01)를 보였다. 200 ${\mu}IU/ml$ 이상 고농도 희석시험에서는 당뇨병환자 검체를 대상으로 했을 때 7개 제조회사 시약 모두 고농도값을 정상적으로 측정하였다. 하지만, 인슐린 종양 검체를 대상으로 측정한 검사에서는 TFB, Siemens, Izotope, Cisbio시약들은 고농도값을 정상적으로 측정하였지만 Biosource와 Immunotech 시약에서 각각 47.4 ${\mu}IU/ml$, 72.3 ${\mu}IU/ml$의 측정치를 보였다. 혈중 Insulin 측정용 방사면역측정법 시약들은 전반적으로 성능이 임상 적용 가능한 범위의 측정 정밀도를 보이면서, 우수한 회수율과 양호한 상관관계를 보였지만 일부 시약에서 고농도 특이검체를 대상으로 Insulin을 측정한 검사에서 고농도값을 제대로 측정하지 못했다. 따라서 여러가지 요인을 놓고 볼 때 비용 효과측면과 자동화 장비에 대한 호환성, 검사 반응시간등 각 검사실 환경에 맞는 시약과 진단적 성능이 보다 우수한 시약을 선정하여 사용한다면 정확하고 신속한 결과보고에 있어서 많은 도움이 된다고 사료된다. Purpose : Serum insulin levels are useful indicator which of reflecting the function of insulin secretion in pancreatic ${\beta}$ cell and diagnosis of diabetes, differentiating the cause of impaired glucose tolerance. Insulin measurement kits have shown some differences in many ways such as test methods as well as quality control. The purpose of this study was to evaluate the diagnostic performance of seven manufacturing companies commercial kits. Materials and Methods : The values of insulin measured by three manufacturing companies (Biosource, Siemens, TFB) with 59 samples in August 2009 were compared with those measured by four manufacturing companies (Immunotech, Izotope, BNIBT, Cisbio) with 68 samples in December 2011. We evaluated precision, recovery rate, dilution test and correlation of serum insulin measurement using seven manufacturing company kits. Statistical program SPSS 12.0 was used for the verification of results. Results : The coefficients variation of the precision on all seven different kits were showed within 5.0%. Recovery rate of Biosource, Siemens, TFB kits on three different levels showed 94.2~103.7%, 99.0~104.6%, 99.7~107.6% respectively. Immunotech, Izotope, BNIBT, Cisbio were 93.5~99.1%, 91.4~99.1%, 99.2~131.0%, 84.8~102.3% respectively. There was strong correlation between the measurement of insulin by Biosource kit and that by two commercial kits, Siemens (R2=0.96), TFB (R2=0.99). There was good correlation between the measurement of insulin by TFB kit and that by three commercial kits, Immunotech (R2=0.97), Izotope (R2=0.96), Cisbio (R2=0.97). In the dilution test performed with more than 200 ${\mu}IU/ml$ high concentration samples, samples with diabetes correctly was measured in all seven manufacturing kits. However, as measured with insulinoma samples TFB, Siemens, Izotope, Cisbio kits were correctly measured, but Biosource and Immunotech kits were measured 47.4 ${\mu}IU/ml$, 72.3 ${\mu}IU/ml$, respectively. Conclusion : Serum Insulin radioimmunoassay kits were showed excellent precision, correlation and good recovery rate. However, some kits were not measured correctly in the high concentration insulin values. when selecting a kit should be considered many factors that cost effectiveness, compatible for automation equipment, high performance kit, the environment for each laboratory such as reaction time and reporting time.

Regulation of Insulin-Sensitive Cyclic Nucleotide Phosphodiesterase in Adipocytes of Streptozotocin-Induced Diabetic Rats

박경선,이명순,김경환,Park, Kyung-Sun,Lee, Myung-Soon,Kim, Kyung-Hwan The Korean Society of Pharmacology 1993 대한약리학잡지 Vol.29 No.2

Streptozotocin으로 당뇨병을 유발시킨 흰쥐를 모델로 하여 당뇨병으로 인한 인슐린의 antilipolytic action을 매개하는 insulin-sensitive cyclic nucleotide phosphodiesterase의 역할의 변화 가능성을 연구하였다. 흰쥐의 epididymal adipose tissue로부터 분리한 지방세포를 여러 약물과 toxin으로 전처치한 다음, insulin을 처치 또는 처치하지 않고 $37^{\circ}C$에서 15분 동안 incubation하였다. 그리고 나서 differential centrifugation으로 3 fractions로 분리한 다음 cAMP phosphodiesterase activity를 assay하였다. Insulin에 의한 PDE activities의 증가는 당뇨병군과 대조군 모두 crude microsomal (P2) fraction에서만 볼 수 있었다. P2 fraction을 2 nM insulin, $100\;{\mu}M$ isoproterenol, 또는 두 약물을 함께 처치하여 나타난 maximal effect는 두 군 모두에서 유의한 차이가 없었다. 그러나 basal PDE activities는 당뇨병균이 대조군에 비해 증가한 것으로 나타났다. 당뇨병군의 P2 fraction의 insulin-sensitive PDE activities는 $A_{1}$ adenosine receptor agonist 인 PIA에 의해서 영향을 받지 않은 반면, 대조군의 경우 PIA에 의해 basal PDE activities와 같게 감소하였다. 그리고 지방세포의 pertussis toxin에 대한 sensitivity는 당뇨병군이 대조군보다 더욱 민감하였다. 그러나 cholera toxin에 대한 sensitivity는 당뇨병군과 대조군 사이에 큰 차이를 볼 수 없었다. 이러한 결과로 보아 streptozotocin으로 당뇨병을 유발시킨 흰쥐의 지방세포에서, adenosine receptor와 같은 inhibitory receptor를 경유한 signalling의 감소는 $G_{i}$ proteins의 소실 또는 기능의 감소와 관련이 있으며, 또한 basal state에서 insulin-dependent PDE의 활성을 증가시키는 것으로 사료된다. Possible changes in the role of insulin-sensitive cyclic nucleotide phosphodiesterase(PDE) in mediating the antilipolytic action of insulin were investigated in adipocytes from streptozotocin-induced diabetic rats. Isolated adipocytes prepared from epididymal adipose tissue were incubated, with or without insulin, at $37^{\circ}C$ for 15 min following pretreatment with various drugs or toxins, and three (plasma membranes, microsomal membranes, and cytosol) fractions prepared by differential centrifugation were then assayed for cAMP phosphodiesterase activity. The PDE activities only in the crude microsomal (P2) fractions were activated by insulin both in diabetic and control rats. The basal PDE activities in P2 fractions of adipocytes from diabetic rats were higher than those from control rats, although the maximal effects observed at 2 nM of insulin, $100\;{\mu}M$ of isoproterenol or the combination of both were not significantly different from each other. The insulin-stimulated PDE activities in P2 fractions of adipocytes from diabetic rats were not changed by PIA, a $A_{1}$ adenosine receptor agonist, whereas they were decreased to the basal PDE activities in those from control rats. In addition, the adipocytes from diabetic rats showed an increased sensitivity to pertussis toxin compared to those from controls. There were no differences between diabetic and control rats in the sensitivity of adipocytes to cholera toxin. These data indicate that the impaired signalling through inhibitory receptors such as adenosine receptors in adipocytes from streptozotocin-induced diabetes relates to the loss or the decreased function of $G_i$ proteins, and leads to the increased activity of the insulin-dependent PDE at the basal states.