GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and ß cells.

Glucose-dependent insulinotropic polypeptide (GIP) communicates nutrient intake from the gut to islets, enabling optimal levels of insulin secretion via the GIP receptor (GIPR) on ß cells. The GIPR is also expressed in α cells, and GIP stimulates glucagon secretion; however, the role of this action in the postprandial state is unknown. Here, we demonstrate that GIP potentiates amino acid-stimulated glucagon secretion, documenting a similar nutrient-dependent action to that described in ß cells. Moreover, we demonstrate that GIP activity in α cells contributes to insulin secretion by invoking paracrine α to ß cell communication. Last, specific loss of GIPR activity in α cells prevents glucagon secretion in response to a meal stimulus, limiting insulin secretion and driving glucose intolerance. Together, these data uncover an important axis by which GIPR activity in α cells is necessary to coordinate the optimal level of both glucagon and insulin secretion to maintain postprandial homeostasis.

Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia.

There is great interest in identifying a glucagon-like peptide-1 (GLP-1)-based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.

Glucagon-like peptide 1 (GLP-1).

BACKGROUND: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent ß-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. SCOPE OF REVIEW: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. MAJOR CONCLUSIONS: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.

Microwave thermal ablation using CT-scanner for predicting the variation of ablated region over time: advantages and limitations.

This study aims at investigating in real-time the structural and dynamical changes occurring in an ex vivo tissue during a microwave thermal ablation (MTA) procedure. The experimental set-up was based on ex vivo liver tissue inserted in a dedicated box, in which 3 fibre-optic (FO) temperature probes were introduced to measure the temperature increase over time. Computed tomography (CT) imaging technique was exploited to experimentally study in real-time the Hounsfield Units (HU) modification occurring during MTA. The collected image data were processed with a dedicated MATLAB tool, developed to analyse the FO positions and HU modifications from the CT images acquired over time before and during the ablation procedures. The radial position of a FO temperature probe (rFO) and the value of HU in the region of interest (ROI) containing the probe (HUo), along with the corresponding value of HU in the contralateral ROI with respect to the MTA antenna applicator (HUc), were determined and registered over time during and after the MTA procedure. Six experiments were conducted to confirm results. The correlation between temperature and the above listed predictors was investigated using univariate and multivariate analysis. At the multivariate analysis, the time, rFO and HUc resulted significant predictive factors of the logarithm of measured temperature. The correlation between predicted and measured temperatures was 0.934 (p  < 0.001). The developed tool allows identifying and registering the image-based parameters useful for predicting the temperature variation over time in each investigated voxel by taking into consideration the HU variation.

Ghrelin.

BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

Clinical evaluation of X-ray voxel Monte Carlo versus pencil beam-based dose calculation in stereotactic body radiotherapy of lung cancer under normal and deep inspiration breath hold.

The purpose of this study is to evaluate the differences between dose distributions calculated with the pencil beam (PB) and X-ray voxel Monte Carlo (MC) algorithms for patients with lung cancer using intensity-modulated radiotherapy (IMRT) or HybridArc techniques. The 2 algorithms were compared in terms of dose-volume histograms, under normal and deep inspiration breath hold, and in terms of the tumor control probability (TCP). The dependence of the differences in tumor volume and location was investigated. Dosimetric validation was performed using Gafchromic EBT3 (International Specialty Products, ISP, Wayne, NJ). Forty-five Computed Tomography (CT) data sets were used for this study; 40 Gy at 8 Gy/fraction was prescribed with 5 noncoplanar 6-MV IMRT beams or 3 to 4 dynamic conformal arcs with 3 to 5 IMRT beams distributed per arc. The plans were first calculated with PB and then recalculated with MC. The difference between the mean tumor doses was approximately 10% ± 4%; these differences were even larger under deep inspiration breath hold. Differences between the mean tumor dose correlated with tumor volume and path length of the beams. The TCP values changed from 99.87% ± 0.24% to 96.78% ± 4.81% for both PB- and MC-calculated plans (P = .009). When a fraction of hypoxic cells was considered, the mean TCP values changed from 76.01% ± 5.83% to 34.78% ± 18.06% for the differently calculated plans (P < .0001). When the plans were renormalized to the same mean dose at the tumor, the mean TCP for oxic cells was 99.05% ± 1.59% and for hypoxic cells was 60.20% ± 9.53%. This study confirms that the MC algorithm adequately accounts for inhomogeneities. The inclusion of the MC in the process of IMRT optimization could represent a further step in the complex problem of determining the optimal treatment plan.

Comparison of insulin glargine and liraglutide added to oral agents in patients with poorly controlled type 2 diabetes.

AIM: To compare safety and efficacy of insulin glargine and liraglutide in patients with type 2 diabetes (T2DM). METHODS: This randomized, multinational, open-label trial included subjects treated for T2DM with metformin ± sulphonylurea, who had glycated haemoglobin (HbA1c) levels of 7.5-12%. Subjects were assigned to 24 weeks of insulin glargine, titrated to target fasting plasma glucose of 4.0-5.5 mmol/L or liraglutide, escalated to the highest approved clinical dose of 1.8 mg daily. The trial was powered to detect superiority of glargine over liraglutide in percentage of people reaching HbA1c <7%. RESULTS: The mean [standard deviation (s.d.)] age of the participants was 57 (9) years, the duration of diabetes was 9 (6) years, body mass index was 31.9 (4.2) kg/m(2) and HbA1c level was 9.0 (1.1)%. Equal numbers (n = 489) were allocated to glargine and liraglutide. Similar numbers of subjects in both groups attained an HbA1c level of <7% (48.4 vs. 45.9%); therefore, superiority of glargine over liraglutide was not observed (p = 0.44). Subjects treated with glargine had greater reductions of HbA1c [-1.94% (0.05) and -1.79% (0.05); p = 0.019] and fasting plasma glucose [6.2 (1.6) and 7.9 (2.2) mmol/L; p < 0.001] than those receiving liraglutide. The liraglutide group reported a greater number of gastrointestinal treatment-emergent adverse events (p < 0.001). The mean (s.d.) weight change was +2.0 (4.0) kg for glargine and -3.0 (3.6) kg for liraglutide (p < 0.001). Symptomatic hypoglycaemia was more common with glargine (p < 0.001). A greater number of subjects in the liraglutide arm withdrew as a result of adverse events (p < 0.001). CONCLUSION: Adding either insulin glargine or liraglutide to subjects with poorly controlled T2DM reduces HbA1c substantially, with nearly half of subjects reaching target levels of 7%.

Physical and dosimetric optimization of laser equipment in dermatology: a preliminary study.

The aim of this preliminary study is to investigate the correlation between clinical set-up at present used in the treatment of specific skin conditions and laser beam absorbed power in the tissue. This study focused on the CO2 and Nd-Yag laser equipment used in the daily clinical practice in the Department of Dermatology of San Gallicano Institute in Rome. Different types of tissue-equivalent material with various water and haemoglobin concentrations were tested to evaluate laser beam attenuation power. In particular, thinly sliced pork loin, of uniform consistency and without fat, was selected for its high content of haemoglobin to mimic human tissues. An optical power meter was used to measure the power or energy of a laser beam. During measurements, the tissue equivalent phantoms were positioned on the detector head and the laser beam was orthogonally oriented. The results of two experimental set-ups are reported here. The dependence of residual power (W) as a function of ex vivo tissue thickness (mm) for different laser output powers was studied. Data were fitted by a parametric logistic equation. These preliminary data allow for more accurately determining the energy fraction released from lasers to the tissues in order to improve clinical outcomes.

Impact of intestinal electrical stimulation on nutrient-induced GLP-1 secretion in vivo.

BACKGROUND: Increases in L-cell release of GLP-1 are proposed to serve as a negative feedback signal for postprandial changes in gastric emptying and/or motility. Previous ex vivo data suggests that direct electrical stimulation (E-stim) of ileal segments stimulates secretion of GLP-1. This suggests potential feed-forward increases in GLP-1 driven by intestinal neuronal and/or motor activity. METHODS: To determine if E-stim could increase GLP-1 levels in an in vivo setting, we administered E-stim and nutrients to male Long- Evans rats (300-350 g) under general anesthesia. KEY RESULTS: Nutrient infusion into the duodenum or ileum significantly increased plasma GLP-1 levels, but E-stim applied to these locations did not (P < 0.05). However, the combination of E-stim and nutrient infusion, in either the ileum or duodenum, significantly increased plasma GLP-1 when compared to nutrient infusion alone (P < 0.05), and this effect was not blocked by either norepinephrine or atropine. To test the impact of intestinal motor activity, the effect of extra-luminal mechanical stimulation (M-stim) on GLP-1 levels was assessed. In the duodenum, but not the ileum, M-stim plus nutrient infusion significantly increased GLP-1 over nutrient infusion or M-stim alone (P < 0.05). CONCLUSIONS & INFERENCES: Thus, both E- and M-stim of the duodenum, but only E-stim of the ileum augmented nutrient-stimulated GLP-1 release. These data demonstrate that factors beyond enteral nutrients could contribute to the regulation of GLP-1 secretion.

Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.

AIMS: To quantify the changes in dose as well as in the prediction of parotid gland toxicity due to anatomical changes during therapy of head and neck cancer patients. MATERIALS AND METHODS: Fifteen patients with advanced locoregional head and neck cancer, with no evidence of distant metastasis, were enrolled in a prospective study. All patients were treated with intensity-modulated radiotherapy. Multiple computed tomography scans were repeated at the end of each treatment week. The original treatment plans were copied to the per-treatment scans to create hybrid plans. The normal tissue complication probability (NTCP) was calculated assuming the end point to be grade ≥3 xerostomia according to the Radiation Therapy Oncology Group late toxicity scale. RESULTS: The gross tumour volume dose coverage was slightly affected by the anatomical changes, whereas the mean dose (D(mean)) to the parotids changed from 26.1 ± 6.0 to 27.4 ± 7.4 Gy, with a mean increase of 0.22 Gy/treatment week. Consequently, the mean NTCP increased from 0.15 ± 0.06 to 0.18 ± 0.10, primarily due to a few patients exhibiting a marked increase. The absolute gross tumour volume shrinkage and the percentage parotids shrinkage were the best independent predictors for the NTCP variations. CONCLUSIONS: On average, the increase in the parotids D(mean) as well as in NTCP during treatment is limited, and the observed variations were strongly patient-dependent.

The role of dysregulated glucagon secretion in type 2 diabetes.

Excessive production of glucose by the liver contributes to fasting and postprandial hyperglycaemia, hallmarks of type 2 diabetes. A central feature of this pathologic response is insufficient hepatic insulin action, due to a combination of insulin resistance and impaired ß-cell function. However, a case can be made that glucagon also plays a role in dysregulated hepatic glucose production and abnormal glucose homeostasis. Plasma glucagon concentrations are inappropriately elevated in diabetic individuals, and α-cell suppression by hyperglycaemia is blunted. Experimental evidence suggests that this contributes to greater rates of hepatic glucose production in the fasting state and attenuated reduction after meals. Recent studies in animal models indicate that reduction of glucagon action can have profound effects to mitigate hyperglycaemia even in the face of severe hypoinsulinaemia. While there are no specific treatments for diabetic patients yet available that act specifically on the glucagon signalling pathway, newer agents including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors reduce plasma glucagon and this is thought to contribute to their action to lower blood glucose. The α-cell and glucagon receptor remain tempting targets for novel diabetes treatments, but it is important to understand the magnitude of benefit new strategies would provide as preclinical models suggest that chronic interference with glucagon action could entail adverse effects as well.

Gender differences in the relationships among obesity, adiponectin and brachial artery distensibility in adolescents and young adults.

BACKGROUND: Obesity-related cardiovascular diseases (CVDs) are a major cause of cardiovascular (CV) mortality. Obesity-related reduction in vascular protective adipose-derived proteins, such as adiponectin (APN), has an important role. METHODS: We compared brachial artery distensibility (BrachD) with APN, the level of adiposity and other CV risk factors (CVRFs) in 431 post-pubertal subjects (mean 17.9 years). Gender differences in average values were examined by t-tests. Correlations among BrachD, obesity and other CVRFs were examined. Regression analysis was performed to determine whether APN provided an independent contribution to BrachD, while controlling for obesity and other CVRFs. RESULTS: Male subjects had lower BrachD (5.72+/-1.37 vs 6.45+/-1.60% change per mm Hg, P<0.0001) and lower APN (10.50+/-4.65 vs 13.20+/-6.53; all P<0.04) than female subjects. BrachD correlated with APN (r=0.25, P< 0.0001). Both BrachD and APN correlated with measures of body size, including height, weight and body mass index (BMI). Both correlated with higher systolic blood pressure, glucose, insulin and lower high-density lipoprotein cholesterol (all P<0.01). In multivariate analysis, APN, gender, APN*gender and BMI z-score predicted BrachD (r(2)=0.305). On the basis of gender difference, only BMI z-score was significant for male subjects (r(2)=0.080), whereas APN and BMI z-score contributed for female subjects (r(2)=0.242, all P<0.0001). CONCLUSIONS: BrachD is independently influenced by obesity in both male and female subjects. In female subjects, APN exerts an additional independent effect even after adjusting for blood pressure (BP), lipid levels and insulin. Differences in the effect of the APN-adiposity relationship on obesity-related vascular disease may be one reason for gender differences in the development and progression of atherosclerosis.

Impaired proinsulin processing is a characteristic of transplanted islets.

We sought to determine whether recipients of islet transplants have defective proinsulin processing. Individuals who had islet allo- or autotransplantation were compared to healthy nondiabetic subjects. Insulin (I), total proinsulin (TP), intact proinsulin and C-peptide (CP) were measured in samples of fasting serum by immunoassay, and the ratios of TP/TP+I and TP/CP were calculated. Islet allotransplant recipients had elevated TP levels relative to nondiabetic controls (16.8 [5.5-28.8] vs. 8.4 [4.0-21.8] pmol/L; p < 0.05) and autologous transplant recipients (7.3 [0.3-82.3] pmol/L; p < 0.05). Islet autotransplant recipients had significantly higher TP/TP+I ratios relative to nondiabetic controls (35.9 +/- 6.4 vs. 13.9 +/- 1.4%; p < 0.001). Islet allotransplant recipients, some of whom were on insulin, tended to have higher TP/TP+I ratios. The TP/CP ratio was significantly higher in both islet autotransplant (8.9 [0.6-105.2]; p < 0.05) and allotransplant recipients (2.4 [0.8-8.8]; p < 0.001) relative to nondiabetic controls (1.4 [0.5-2.6]%). Consistent with these findings, TP/TP+I and TP/CP values in islet autotransplant recipients increased significantly by 1-year posttransplant compared to preoperative levels (TP/CP: 3.8 +/- 0.6 vs. 23.3 +/- 7.9%; p < 0.05). Both allo- and autotransplant subjects who received <10,000 IE/kg had higher TP/CP ratios than those who received >10,000 IE/kg. Islet transplant recipients exhibit defects in the processing of proinsulin similar to that observed in subjects with type 2 diabetes manifest as higher levels of total proinsulin and increased TP/TP+I and TP/CP ratios.

Failure of glucagon-like peptide-1 to induce panic attacks or anxiety in patients with panic disorder.

The insulin secretogogue glucagon like peptide-1 (GLP-1), as well as agents which enhance GLP-1 signaling, are being studied as potential treatments for diabetes. Pre-clinical evidence suggests that these agents may have neuropsychiatric side effects; however, there have been no investigations or reports of these effects in humans. We evaluated possible anxiogenic and panicogenic properties of GLP-1 in 9 healthy subjects (age 47+/-8 years) and 7 patients with panic disorder (age 38+/-17 years) using a single-blinded intravenous GLP-1 challenge (2pmol/kg/min over 60min). We assessed the occurrence of panic attacks during and after GLP-1 infusion and the emergence of anxiety or panic symptoms using the Acute Panic Inventory (API). No patient or healthy subject experienced any panic attacks at any point during this study. Moreover, there were no significant changes in API scores following the infusion in either group. These data suggest that in humans, intraveneously administered GLP-1 does not appear to have anxiogenic or panicogenic properties, even in patients at highest risk for such reactions.

Effect of human body weight changes on circulating levels of peptide YY and peptide YY3-36.

BACKGROUND: Recent findings suggest that low plasma peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY(1-36) and the pharmacologically active PYY(3-36) is indicated to determine the potential role in energy balance regulation. AIM: Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone peptide YY. DESIGN: Total plasma PYY levels (PYY(1-36) + PYY(3-36)) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY(3-36) levels were measured in 17 lean and 15 obese individuals. RESULTS: Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 +/- 12.9 pg/ml, P < 0.05) compared with lean (52.4 +/- 4.6 pg/ml), obese (43.9 +/- 3.8 pg/ml), or morbidly obese (45.6 +/- 11.2 pg/ml) subjects. In obese patients, weight loss of 5.4% was associated with a 30% decrease in fasting total PYY plasma levels. In anorectic patients, weight gain had no effect on fasting PYY. PYY(3-36) levels did not differ between lean (96.2 +/- 8.6 pg/ml) and obese (91.5 +/- 6.9 pg/ml) subjects. CONCLUSION: Our findings do not support a role for abnormal circulating PYY in human obesity. We conclude that circulating PYY levels in humans are significantly elevated in anorexia nervosa and, given the controversially discussed anorectic effect of PYY, could theoretically contribute to that syndrome.

Effects of glucagon-like peptide 1 on the hepatic glucose metabolism.

Glucagon-like peptide 1 has important actions in lowering blood glucose, both through its incretin action and by regulating other systems affecting glucose metabolism. There is good evidence that the coordinate regulation of islet hormones by GLP-1 has significant effects on hepatic glucose metabolism, and this likely contributes to the potent effect of GLP-1 on fasting hyperglycemia in diabetic patients. More controversial are potential effects of GLP-1 on hepatic glucose production or storage independent of insulin and glucagon. There are data from in vitro studies supporting an effect of GLP-1 to promote glycogen synthesis in hepatocytes, and several in vivo studies suggesting that GLP-1 has independent effects on hepatic glucose uptake and/or production. However, these findings must be considered against a backdrop of studies that have not demonstrated islet-independent actions of GLP-1. This paper will review the current literature addressing hepatic effects of GLP-1 and identify important gaps in the knowledge base for this topic.

Recombinant glucagon-like peptide-1 (7-36 amide) lowers fasting serum glucose in a broad spectrum of patients with type 2 diabetes.

AIMS: To evaluate the safety and efficacy of various doses of recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered subcutaneously (s. c.) via bolus injection or continuous infusion to lower fasting serum glucose (FSG) levels in subjects with type 2 diabetes treated by diet, hypoglycemic drugs, or insulin injection. METHODS: rGLP-1 was administered s. c. to 40 type 2 diabetics currently treated by diet, sulfonylurea (SU), metformin, or insulin in a double-blind, placebo-controlled, cross-over trial; preexisting treatments were continued during the study. In the bolus injection protocol, 32 subjects (8 from each of the 4 treatment groups) received 0.0, 0.5, 1.0, and 1.5 nmol rGLP-1/kg per injection (two injections, two hours apart, beginning one hour after the evening meal) in a randomized order on separate days. In the continuous s. c. infusion protocol, 40 subjects received rGLP-1 at 0.0, 1.5, 2.5, 3.5, and 4.5 pmol/kg/min for 10-12 hours overnight starting one hour after the evening meal. Fasting bloods were taken the morning after for glucose, insulin, and glucagon measurements. RESULTS: In the diet, SU, and metformin cohorts, bolus rGLP-1 injections produced modest reductions in mean FSG levels, averaging 17.4 mg/dl (7.3-27.5; 95 % CI) at the highest dose (p < 0.001 vs. placebo). Reductions in FSG levels were greater by continuous infusion at up to 30.3 mg/dl (18.8 - 41.8; 95 % CI; p < 0.001 vs. placebo). The greatest reduction in mean FSG occurred in the SU cohort (up to 43.9 mg/dl, 24.7 - 63.1; 95 % CI; p < 0.001). rGLP-1 infusions resulted in significant increases in fasting plasma insulin and decreases in fasting plasma glucagon levels. There were no serious adverse events; GI-related symptoms were dose-related and more commonly associated with injections. CONCLUSIONS: rGLP-1 (7-36) amide dose-dependently lowered FSG in a broad spectrum of type 2 diabetics when added to their existing treatment. Subcutaneous infusion was more effective than injection, and the combination with SU was more effective than with metformin.

Impaired insulin response after oral but not intravenous glucose in heart- and liver-transplant recipients.

BACKGROUND: The prevalence of diabetes is high after transplantation. We hypothesized that liver transplantation induces additional alterations of glucose homeostasis because of liver denervation. METHODS: Nondiabetic patients with a heart (n=9) or liver (n=9) transplant and healthy subjects (n=8) were assessed using a two-step hyperglycemic clamp (7.5 and 10 mmol/L). Thereafter, an oral glucose load (0.65 g/kg fat free mass) was administered while glucose was clamped at 10 mmol/L. Glucose appearance from the gut was calculated as the difference between glucose appearance (6,6 2H2 glucose) and exogenous glucose infusion. Plasma insulin, glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide(GIP) concentrations were compared after intravenous and oral glucose. RESULTS: After oral glucose, the glucose appearance from the gut was increased 52% and 81% in liver- and heart-transplant recipients (P<0.05). First-pass splanchnic glucose uptake was reduced by 39% in liver-transplant and 64% in heart-transplant patients (P<0.05). After oral but not intravenous glucose, there was an impairment of insulin secretion in both transplant groups relative to the controls. Plasma concentrations of GIP and GLP-1 increased similarly in all three groups after oral glucose. CONCLUSIONS: First-pass hepatic glucose extraction is decreased after heart and liver transplant. Insulin secretion elicited by oral, but not intravenous glucose, is significantly reduced in both groups of patients. There was no difference between liver- and heart-transplant recipients, indicating that hepatic denervation was not involved. These data suggest an impairment in the beta-cell response to neural factors or incretin hormones secondary to immunosuppressive treatment.

Increasing incidence of end-stage renal disease in Wisconsin: an unintended consequence of increased survival?

End stage renal disease (ESRD) is an important and costly complication of diabetes, hypertension, and primary kidney disorders. We examined ESRD incidence trends in Wisconsin from 1982 to 1997 and assessed the progress in reaching the ESRD 2000 goal as stated by Healthier People in Wisconsin: A Public Health Agenda for the Year 2000. Since 1982, there has been nearly a three-fold increase in the incidence of ESRD in Wisconsin. The increase was most striking in persons with diabetes and among people age 65 and older. Furthermore, the increase was shared among all racial groups and both genders. Although better disease management reduces the risk of ESRD, it also reduces the risk of other causes of death such as heart disease and cancer. Thus, individuals may be living longer with other chronic diseases, thereby increasing the incidence of ESRD.

Risk factors for frequent and severe hypoglycemia in type 1 diabetes.

OBJECTIVE: To determine the risk of frequent and severe hypoglycemia and the associated demographic and clinical risk factors. RESEARCH DESIGN AND METHODS: Demographic and diabetes self-management factors were measured in 415 subjects followed prospectively for 4-6.5 years of type 1 diabetes duration as participants in a population-based incident cohort. Blood samples were collected up to three times yearly to test glycosylated hemoglobin (GHb) levels. Reports of frequent (2-4 times/week) and severe (lost consciousness) hypoglycemia as well as other diabetes self-management data were collected by questionnaires. RESULTS: Frequent hypoglycemia was common (33 and 35% of participants reported this on the 4- and 6.5-year questionnaires, respectively), whereas severe hypoglycemia occurred much less often. Better glycemic control (odds ratio [OR] 1.3 per 2% decrease in GHb, 95% CI 1.1-1.5) and more frequent self-monitored blood glucose (1.5 per blood glucose check, 1.3-1.7) were independently related to frequent hypoglycemia. The association of frequent hypoglycemia with intensive insulin therapy increased with age. Better glycemic control (1.5 per 2% decrease in GHb, 1.2-2.0) and older age were related to severe hypoglycemic reactions. No sociodemographic factors other than age increased the risk of hypoglycemia. CONCLUSIONS: Frequent hypoglycemia was common in a population representing the full range of glycemic control in the community. Intensive insulin management and blood glucose monitoring independently predicted frequent but not severe hypoglycemia. This information may be useful for updating patients such that minor changes in diabetes management might decrease the daily burden of this condition while maintaining intensive insulin therapy.