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Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting.In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed.A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group.In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

Background: Ectopic production of ACTH causing Cushing’s syndrome (CS) is rare but has been well described in association with bronchial carcinoids, thymomas, pancreatic malignancies, and small cell lung carcinomas. We report a rare case of CS caused by ACTH-producing non-small cell carcinoma. Clinical Case: A 71 year-old man with a history of squamous cell carcinoma of the lung (T2bN1M0) 10 years prior who underwent lobectomy and adjunctive chemotherapy, presented with a new cough, weight loss, and bilateral lower extremity edema. He was also noted to have significant fatigue, hypertension, symptomatic hyperglycemia, and hypokalemia. CT chest revealed a large right perihilar mass with mediastinal adenopathy and numerous hepatic lesions. A biopsy of the liver lesions revealed a poorly differentiated carcinoma with neuroendocrine features strongly positive for AE1/3 with focal p40+, CK7, synaptophysin, chromogranin, and TTF1. It was negative for p63, CK5/6, CDX2, CK20, and GATA3. The morphology and immunohistochemical staining favored a squamous primary. Unfortunately, there was insufficient tissue sample to stain for ACTH. Biochemical evaluation revealed: post-1 mg dexamethasone serum cortisol 74.8 µg/dL (N < 1.8 µg/dL), 24 hr urine free cortisol 2987 µg/g creatinine (normal: < 32 µg/g creatinine), and ACTH 170 pg/mL (N < 47 pg/mL). Other notable findings at presentation were potassium 2.8 mmol/L (N: 3.7-5.1 mmol/L) and glucose 371 mg/dL (N: 74-99 mg/dL). MRI brain revealed focal pituitary infundibular thickening up to 6 mm in diameter and an enlargement of the pituitary gland concerning for metastasis. The patient’s clinical course was complicated by persistent hypokalemia and hyperglycemia which were treated with spironolactone 100 mg twice a day and insulin therapy, respectively. Ketoconazole 100 mg twice a day was initiated for the hypercortisolemia; etoposide, carboplatin, and atezolizumab were started for the neuroendocrine tumor. The patient expired due to sepsis one month after the diagnosis of Cushing’s syndrome. Conclusion: We report a rare case of paraneoplastic Cushing’s syndrome due to poorly differentiated neuroendocrine tumor with a squamous cell carcinoma primary. ACTH producing non-small cell carcinomas have been seldom reported in the literature. Although we were unable to provide ACTH staining on pathology, the existence of an obvious neuroendocrine tumor, marked elevation in ACTH, and an MRI which was negative for a pituitary adenoma, strongly suggests paraneoplastic Cushing’s syndrome.

Islam is the second most common religion in the world, and there are 1.6 billion Muslims, many in areas where diabetes is prevalent. Each year observant Muslims fast during the daylight hours for the holy month of Ramadan. It is estimated that 50 million diabetic people fast between dawn and sundown

The prevalence and clinical significance of incidental differentiated thyroid cancer (DTC) in patients with Graves' disease (GD) remain uncertain. Thyroid stimulating antibody (TSI Ab)-titers were thought to be responsible for the potentially increased incidence or aggressiveness of PTC in that setting. The aim of this study was to compare the prevalence of incidental DTC among patients with GD and euthyroid goiter (EG), to assess the ability of TSI to predict DTC in GD and to investigate the clinical features that may predict incidental DTC in GD and EG.Two hundred and forty eight patients with EG and 245 patients with GD patients who had undergone total thyroidectomy at our institution between 2005 and 2013 were retrospectively selected from our data base. An analysis of incidentally discovered DTC was conducted comparing GD group with EG group.Incidental micro-papillary thyroid cancer (MPTC) was found in 28% in EG group, as compared to 26% in GD group. PTC Patients with GD were significantly younger (44 vs 59) and less likely to have compressive symptoms than with EG before surgery (p0.001). In GD group, patients with MPTC were also significantly older (p=0.009) than those without, were more likely to have symptomatic goiter (p0.001), and to have a nodular disease (p0.001). TSI ab titer did not predict MPTC in GD group (The AUC curve was 0.55 (95% CI: 0.46, 0.64). Among patients with GD and incidental MPTC, 58% of patients had at least one nodule.The prevalence of incidental DTC in GD is comparable to EG. Each is increased compared to general population. Age of presentation of PTC was significantly lower in GD suggesting an increased risk for MPTC in GD. Nodule size greater than 1cm predicted incidental DTC whereas TSI ab titers and disease duration did not.

BACKGROUND AND OBJECTIVE: The purpose of this study was to identify whether endocrinologists and primary care physicians (PCP) adequately screen for ophthalmic symptoms/signs within office visits and provide timely ophthalmology referrals in patients with diabetes. PATIENTS AND METHODS: Patients between the ages of 18 years and 80 years with diabetes who underwent an office visit with an endocrinologist or a PCP between January 1, 2014, and December 31, 2014, were identified. Demographics, ophthalmic assessments, and referral information were collected. RESULTS: A total of 1,250 patient records were reviewed. Providers asked about ophthalmic symptoms/signs in 95.5% and 71% of endocrinology and primary care office encounters, respectively ( P < .0001). Past and/or future ophthalmology appointments were verified in 86.1% and 49.7% of patients during endocrinology and PCP visits, respectively ( P < .0001). CONCLUSIONS: Ophthalmic complications from diabetes are not adequately screened, especially within the primary care setting, and further quality improvement measures may improve adherence to recommended screening protocols. [ Ophthalmic Surg Lasers Imaging Retina . 2016;47:930–934.]

Objective To review the literature regarding the use of insulin glargine during pregnancy, specifically addressing the issues and concerns surrounding mitogenicity, placental transfer, and maternal and fetal safety. Methods We performed a systematic literature search using MEDLINE and BIOSIS Previews up to March 2011. Additional studies were identified by hand-searching reference lists from original articles. Inclusion was limited to studies and abstracts in the English language. Results A total of 23 reports with 1001 pregnancies managed with insulin glargine contained relevant information regarding the maternal and fetal safety of its use during pregnancy. Insulin glargine does not appear to have enhanced mitogenic activity when compared with the mitogenic activity of native human insulin. The transplacental transfer of insulin glargine appears to be negligible, although it is possible that antibody-bound insulin glargine may gain access to the fetal compartment. The available data suggest that there are no identifiable, consistent adverse maternal or fetal outcomes with the use of insulin glargine during pregnancy, including during the first trimester. Conclusions Use of insulin glargine during pregnancy should be seriously considered in uncontrolled diabetes during pregnancy and in those patients taking insulin glargine before conception, because the benefits from improved glycemic control would be expected to outweigh any, as yet, unproven risks of insulin glargine exposure. (Endocr Pract. 2011;17:448-455)

Background: The importance of near-normal blood glucose in the immediate postoperative period is generally accepted and is best achieved in the perioperative period with a constant intravenous (IV) infusion of insulin. This requires intensive nursing only achievable in an intensive care unit (ICU) setting. Glucose management after transfer to a regular nursing floor (RNF) has not been studied systematically. In August 2006, the Cleveland Clinic began using long-acting insulin glargine as the insulin infusion was terminated in the ICU. Methods: This prospective analysis examined all patients receiving IV insulin infusion after cardiothoracic surgery in a 1 month period. The analyses evaluated the safety and efficacy of a protocol using a transition to subcutaneous insulin glargine of 50% of the calculated 24 h requirement at the end of the ICU insulin infusion protocol in preparation for transfer to the RNF. Results: Only 1 patient in 99 developed hypoglycemia, and no patient suffered severe hypoglycemia (glucose < 40 mg/dl), while the majority (70%) had euglycemia (glucose between 70 and 150 mg/dl). Conclusions: This approach was both safe—as there was very little hypoglycemia (1 patient in 99)—and effective, as blood sugar was well controlled in most subjects. Efficacy for achieving euglycemia was 70%. Efficacy was likely reduced because of the upper limit of insulin glargine dosage imposed by some providers as a safety consideration. Although there was a physician option to override, the maximum protocol dose of 30 U was rarely exceeded, leading to inadequate dosing in some subjects who required high insulin infusion rates in the ICU.

Original absorption studies for levothyroxine (LT4) were validated using total thyroxine (TT4) measurements. Free thyroxine (FT4) has largely supplanted TT4 in clinical practice. The objective of our study was to assess the clinical utility of FT4 in oral LT4 absorption testing.In this retrospective electronic health record analysis, we recorded data of patients who underwent LT4 oral absorption testing between November 2010 and January 2012 because of persistent hypothyroidism despite a greater than anticipated weight-based dose of LT4. Patients included had primary hypothyroidism and an absorption test with assessment of both TT4 and FT4 measured at times 0, 30, 60, 90, 120, 180, 240, 300, and 360 minutes. The test was conducted with 1 mg (five 200-μg tablets) of Synthroid® after an overnight fast by a standard nonisotopic method.A total of 10 patients (3 men/7 women) underwent absorption testing. Prior to testing, the median daily LT4 dose was 250 μg (range, 150 to 350 μg). Three patients were also on liothyronine (10, 20, or 50 μg daily). Based on the calculated amount absorbed, 1 patient demonstrated subnormal absorption, and 9 patients were normal. Median body mass index was 33 kg/m2 (range, 21 to 50 kg/m2). Median calculated absorption was 105% (range, 3.7 to 195.6%). The correlation comparing FT4 and TT4 was 0.88 (95% confidence interval, 0.56 to 0.97; P.001), a significant correlation.FT4 and TT4 correlated highly, even in patients who were severely hypothyroid; FT4 may be used interchangeably with TT4 as a qualitative assessment of suspected malabsorption using an oral LT4 absorption test.

Prolactin has been proposed as a potent coactivator of platelet aggregation, possibly contributing to thromboembolic events. The objective of the study was to evaluate the relationship between prolactinoma and deep vein thrombosis (DVT), pulmonary embolism (PE), and cerebrovascular accident (CVA). Subjects were identified from a prospectively maintained pituitary database at the Cleveland Clinic. We retrospectively reviewed the charts of 544 subjects: 347 patients with prolactinomas (prolactinoma group) and 197 patients with nonfunctional pituitary adenomas (control group). Main outcome measures were DVT, PE and CVA. We found that 19 (5.5 %) patients in the prolactinoma group and five (2.5 %) patients in the control group had documented DVT, PE, or CVA, but this difference was not significant (p = 0.109). However, the mean initial prolactin level was higher at the time of diagnosis among prolactinoma patients than among controls (815.23 ng/ml vs. 15.90 ng/ml; p < 0.001). Among prolactinoma patients, 15 (5.5 %) of 275 patients who underwent medical treatment (with cabergoline, bromocriptine, pergolide and/or other drug) and 4 (5.6 %) of 72 patients who underwent transsphenoidal surgery had documented DVT, PE, or CVA, which suggests that dopaminergic therapy did not influence the risk of thromboembolic events. Hyperprolactinemia per se does not appear to predispose to a hypercoagulable state.

About a decade ago, a question was raised about glyburide, a widely used sulfonylurea, as a possible cause for acute pancreatitis (Blomgren). Since then, several systemic reviews reveal the incidence of acute pancreatitis in patients with type 2 diabetes 1.5 to 3-fold increase risk compared to non-diabetic subjects in each of 3 large health data bases (Noel, Garg, Girman). Five years after the concern was raised about glyburide and soon after the first of the incretin based, exenatide, had gained a significant market share, reports of pancreatitis again began to surface. This was followed by a similar concern when the first in class of the next new class of diabetes agents, the dipeptyl depeditidase-4 inhibitor (DPP-4 inhibitor), sitagliptin had achieved a significant market share. Exenatide is a glucagon like peptide one (GLP-1) agonist and DPP-4 inhibitors increase to action of endogenous GLP-1 by slowing the degradation of endogenous GLP-1, as well of other gut derived hormones, so a common etiology was implied. Examination of two different insurance data bases, again reveal no real increase over other agents used to treat type 2 diabetes. Review of the incidence of acute pancreatitis from the adverse event data from the clinical trials of the two GLP-1 agonists and the three DPP-4 inhibitors available currently on the US market reveals similar rates of acute pancreatitis with each agent and with the comparators during blinded clinical trials, providing more evidence that it is the disease state, not the agent causing the increase in incidence. This chapter will cover the wide variety of drugs that have been associated with acute pancreatitis as well as the studies that substantiate increase in acute pancreatitis in type 2 diabetes. The rate of acute pancreatits in incretin based agents and other agents as mentioned above seems the same as the rate in the population of type 2 diabetic as a whole. The rates of acute pancreatitis from clinical trial data of the five agents available in the US and the comparators afford the best prospective data on this subject.

A 56-year-old woman presents with proximal weakness in all four limbs. What are the possible causes?

Growth hormone (GH) producing adenomas of the pituitary gland are usually macroadenomas (>10 mm in size). Often these adenomas are locally invasive by the time of diagnosis. Acromegaly secondary to a very small pituitary microadenoma not visualized on pituitary magnetic resonance (MR) imaging is rare. We report a patient with acromegaly and an unremarkable pituitary MR imaging who had negative work up for ectopic growth hormone-releasing hormone (GHRH) or GH secreting tumors. Transsphenoidal pituitary exploration revealed a pituitary adenoma located on the left side of the sella against the medial wall of the cavernous sinus extending posteriorly along the floor of the sella all the way to the right side. The acromegaly was treated with resection of the pituitary adenoma and normalization of serum insulin-like growth factor 1 (IGF-1) and GH levels. In a patient with acromegaly and unremarkable pituitary MR imaging, with no evidence of ectopic GH and GHRH production, transsphenoidal pituitary exploration is a reasonable approach and may result in clinical improvement and biochemical cure in the hand of experienced surgeon. This approach may avoid long term medical treatment with its associated cost.

Myocarditis, often initiated by viral infection, may progress to autoimmune inflammatory heart disease, dilated cardiomyopathy and heart failure. Although cardiac myosin is a dominant autoantigen in animal models of myocarditis and is released from the heart during viral myocarditis, the characterization, role and significance of anti-cardiac myosin autoantibodies is poorly defined. In our study, we define the human cardiac myosin epitopes in human myocarditis and cardiomyopathies and establish a mechanism to explain how anti-cardiac myosin autoantibodies may contribute to heart disease. We show that autoantibodies to cardiac myosin in sera from myocarditis and dilated cardiomyopathies in humans targeted primarily epitopes in the S2 hinge region of cardiac myosin. In addition, anti-cardiac myosin antibodies in sera or purified IgG from myocarditis and cardiomyopathy targeted the beta-adrenergic receptor and induced antibody-mediated cAMP-dependent protein kinase A (PKA) cell signaling activity in heart cells. Antibody-mediated PKA activity in sera was abrogated by absorption with anti-human IgG. Antibody-mediated cell signaling of PKA was blocked by antigen-specific inhibition by human cardiac myosin or the beta-adrenergic receptor but not the alpha adrenergic receptor or bovine serum albumin. Propranolol, a beta blocker and inhibitor of the beta-adrenergic receptor pathway also blocked the antibody-mediated signaling of the beta-adrenergic receptor and PKA. The data suggest that IgG antibody against human cardiac myosin reacts with the beta-adrenergic receptor and triggers PKA signaling in heart cells. In-summary, we have identified a new class of crossreactive autoantibodies against human cardiac myosin and the beta-adrenergic receptor in the heart. In addition, we have defined disease specific peptide epitopes in the human cardiac myosin rod S2 region in human myocarditis and cardiomyopathy as well as a mechanistic role of autoantibody in the pathogenesis of disease.

Coated-platelet levels were quantified in 58 people with Type 1 diabetes, 90 with Type 2 diabetes, and 54 non-diabetic controls. In diabetes high coated-platelet levels were related to smoking and glucose control drugs, but not to glycaemia or other drugs. Prospective studies should evaluate coated-platelets and complications and drug effects.

Intravenous infusion of epinephrine or norepinephrine produces hypertension and symptoms similar to a pheochromocytoma.1,2 The sequelae are predictable on the basis of continuous infusion of agonists that activate β and α adrenergic receptors (ARs). These monoamine agonists, however, are not the only means by which β-ARs can be activated. Activating autoantibodies (AAs) directed toward the β1AR and/or the β2AR have been demonstrated in some patients with idiopathic dilated cardiomyopathy,3–5 Chagas’ disease,6,7 and other forms of cardiomyopathy.8,9 Several studies have demonstrated that these antibodies possess the ability to activate the intrinsic βAR signal transduction system; however, these studies have focused only on the possible relationship of the AAβAR agonist effects on cardiomyopathy. Because β-agonist excess also produces changes in systemic blood pressure, one would expect the presence of AAβAR to produce a phenotype including some features observed in patients with an epinephrine-only secretory neuroendocrine tumor. Isolated studies have reported the concurrence of activating autoantibodies to the α1AR10,11 or to the angiotensin receptor (AT1)12,13 in a few patients with associated hypertension. Herein, we present a hypertensive patient with no clinical evidence for a pheochromocytoma secreting excess catecholamine(s). However, in year 2000, there was conclusive evidence for anti-βAR autoantibodies, which in vitro activate the βAR signal transduction system independent of the intrinsic hormone-mediated system. Subsequent study in sera obtained in 2006 confirmed these data. These autoantibodies, as a result of their peptide sequence specificity, do not activate the α-adrenergic transduction system, as would norepinephrine or epinephrine at higher dosages. The evidence that these antibodies possess all of the β-activation potential of epinephrine is not unlike that expected with an epinephrine-only secreting pheochromocytoma but without a secretory tumor. The patient may represent the prototype of a new hypertensive syndrome that has an …

The incidence of tall cell variant of papillary thyroid carcinoma that has metastasized to the pancreas is extremely rare. There has been only one previously reported case of pancreatic metastasis of the tall cell variant of papillary thyroid carcinoma.We present the case of a patient who presented with tall cell variant of papillary thyroid carcinoma with metastasis to the pancreas detected and confirmed cytologically by EUS-FNA after finding of the CT scan were equivocal.EUS-FNA is a powerful new tool that can be used for the detection and diagnosis of primary and metastatic lesions of the pancreas.

Background : Thiazolidinediones (TZDs) have contributed to the management of patients with type 2 diabetes mellitus as unique insulin-sensitizing agents. When used as monotherapy or in combination therapy, these drugs not only reduce glycosylated hemoglobin (HbA 1c ) levels, but also effect changes in blood lipid concentrations and have the potential to ameliorate cardiovascular disease risk. Although drugs in the TZD class are perceived to be equivalent clinically, prospective and retrospective studies have demonstrated their ability to modify blood lipid levels. Objective : We evaluated and compared the effects of pioglitazone and rosiglitazone monotherapy and combination therapy on blood lipid levels and HbA 1c in patients with type 2 diabetes. Methods : We conducted a multicenter retrospective chart review of 1115 records of patients with type 2 diabetes who received pioglitazone or rosiglitazone, alone or in combination with other antidiabetic agents, between August 1, 1999, and August 31, 2000. The review was conducted to evaluate pretreatment and posttreatment levels of triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and HbA 1c . Results : All observed demographic characteristics, comorbidities, and concomitant drug use were similar in both treatment cohorts. Of the patients who received pioglitazone, 83% also received >_1 other antihyperglycemic agent and 59% received some form of antihyperlipidemic therapy. Among those who received rosiglitazone, 81% received concomitant antihyperglycemic medication and 60% received some form of antihyperlipidemic therapy. With pioglitazone, mean levels of serum triglyceride, total cholesterol, and LDL-C decreased and HDL-C increased in most patients, with or without concomitant antihyperglycemic medications; with rosiglitazone, with or without other antidiabetic agents, triglyceride and HDL-C levels decreased, whereas total cholesterol and LDL-C levels increased in most patients. Reductions in HbA 1c levels and increases in body weight related to each study drug were comparable. Conclusions : This comparative assessment of pioglitazone and rosiglitazone, based on observational data, reveals that use of these TZDs with other antidiabetic agents was similar in 605 primary care practices in the United States. In both monotherapy and combination treatment regimens, pioglitazone was associated with greater beneficial effects on lipids than was rosiglitazone. Additional studies are needed to determine the long-term outcomes of TZD therapy with concomitant antihyperglycemic medications.

Background: The antihyperglycemic effects of pioglitazone hydrochloride and rosiglitazone maleate are well documented. The results of clinical trials and observational studies have suggested, however, that there are individual differences in the effects of these drugs on blood lipid levels. Objective: The present study evaluated the effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus. Methods: This was a retrospective review of randomly selected medical records from 605 primary care practices in the United States in which adults with type 2 diabetes received pioglitazone or rosiglitazone between August 1, 1999, and August 31, 2000. The outcome measures were mean changes in serum concentrations of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glycosylated hemoglobin (HbA 1c ) values. Results: Treatment with pioglitazone was associated with a reduction in mean TG of 55.17 mg/dL, a reduction in TC of 8.45 mg/dL, an increase in HDL-C of 2.65 mg/dL, and a reduction in LDL-C of 5.05 mg/dL. Treatment with rosiglitazone was associated with a reduction in mean TG of 13.34 mg/dL, an increase in TC of 4.81 mg/dL, a reduction in HDL-C of 0.12 mg/dL, and an increase in LDL-C of 3.56 mg/dL. With the exception of HDL-C, the differences in mean changes in lipid parameters between treatment groups were statistically significantly ( P 1c were statistically equivalent between treatments (1.04% pioglitazone, 1.18% rosiglitazone). Conclusions: Treatment with pioglitazone was associated with greater beneficial effects on blood lipid levels than treatment with rosiglitazone, whereas glycemic control was equivalent between the 2 treatments.

In 2007 a question was raised about the causal relationship between the first of the glucagon-like peptide 1 receptor agonists, exenatide, and pancreatitis, as postmarketing reports of pancreatitis in patients treated with this agent had been received by the Food and Drug Administration (FDA). There had been six reports of hemorrhagic pancreatitis, with two of the cases resulting in death. An update of the package insert for Byetta was mandated. Sitagliptin entered the market about a year and a half later, and now there are similar reports of acute pancreatitis. As the number of patients treated with these agents increases, is it uncovering a risk not appreciated in the premarket phase or just what should be expected from the population treated with these agents? To date, 88 cases of acute pancreatitis have been reported to the FDA in patients taking sitagliptin (Januvia/Janumet). Of these, two cases have been hemorrhagic or necrotizing pancreatitis. A revision of the package insert for sitagliptin has been made recently. An examination of available data should help shed light on whether the relation is likely causal or merely incidental.

Synthetic bovine parathyroid hormone containing the 1–34 NH2-terminal amino acids [bPTH-(1-34)] inhibits uterine contraction stimulated by a variety of agonists. Previously, we reported tha

Cultured 3T3-L1 cells provide a model system for studies of the long-term regulation of lipolysis. Insulin acutely inhibits isoproterenol-stimulated lipolysis primarily by decreasing the apparent affinity apparent Km for isoproterenol. In contrast, chronic insulin exposure inhibits lipolysis by a reduction in the maximal effect of isoproterenol Vmax. The decrease in Vmax can be observed with insulin concentrations that are as low as 10−9 mol/L at the time of addition. The effect is stable to washing, and the cells' responsiveness to isoproterenol returns partially with continued culture. Chronic insulin exposure also markedly reduced dibutyryl-cAMP-stimulated lipolysis indicating an insulin-induced change distal to cAMP concentration in the cascade of reactions controlling lipolysis in these cells. Time course and insulin dose-response experiments indicate an additional proximal alteration. These results indicate that: (1) 3T3-L1 cells are a useful model for studying the long-term regulation of lipolysis. (2) Chronic insulin exposure inhibits lipolysis by a mechanism that differs from the acute effect of insulin. (3) The chronic effects of insulin may be mediated through changes at multiple levels in the lipolytic cascade.

Pertussis toxin (PT), a protein produced by Bordetella pertussis, was studied for its effect on lipolysis in isolated rat epididymal adipocytes. Exposure of adipocytes to pertussis toxin resulted in a significant increase in cyclic AMP levels and lipolysis after a lag of 1-2 hr. Both the maximal rate of lipolysis and the time lag (beyond 1 hr) were PT concentration-dependent. Heat treatment (95 degrees C, 30 min) or incubation with specific antibody directed against PT eliminated the ability of toxin to increase lipolysis. Cell-free culture medium from B. pertussis, but not from nontoxigenic Bordetella species, had the same effect on lipolysis as purified toxin. Comparison of the PT effect with the known lipolytic effect of cholera toxin (CT) revealed that the two toxins elicited responses that were indistinguishable in time course and magnitude. In contrast, the adenylate cyclase (EC 4.6.1.1) activities in membranes prepared from PT- or CT-treated adipocytes were different. Adenylate cyclase activity in membranes from control (untreated) adipocytes was inhibited 35-64% by the adenosine analogue N6-(L-2-phenylisopropyl)-adenosine. As expected from previous studies, membranes from CT-treated adipocytes demonstrated an increased basal activity but showed the same proportional inhibition by N6-(L-2-phenylisopropyl)-adenosine as controls. On the other hand, membranes from adipocytes exposed to PT (400 ng/ml for 4 hr) showed no increase in basal adenylate cyclase activity but had reduced sensitivity to N6-(L-2-phenylisopropyl)-adenosine inhibition, with the maximal effect ranging from 11 to 30% at 10(-6) M N6-(L-2-phenylisopropyl)-adenosine. These data support the hypothesis that PT promotes cyclic AMP-dependent lipolysis in a manner quantitatively equivalent to CT, but by a different mechanism involving increased cyclic AMP levels resulting from loss of responsiveness to endogenous inhibitors such as adenosine.