Efficacy and Safety of 6-Month High Dietary Protein Intake in Hospitalized Adults Aged 75 or Older at Nutritional Risk: An Exploratory, Randomized, Controlled Study.

The aim of this study was to investigate the effects of increased dietary protein in daily-life settings in Japan for 6 months on the activities of daily living (ADL) in adults aged 75 or older at nutritional risk. The study was an open-label, exploratory, randomized controlled trial conducted at seven hospitals in Japan. The study participants were adults aged 75 or older who were hospitalized for treatable cancer, pneumonia, fractures, and/or urinary-tract infection at nutritional risk. The primary outcome was change in grip strength, skeletal muscle, and ADL indices (Barthel index, Lawton score). One hundred sixty-nine patients were randomly assigned to the intensive care (IC) or standard care (SC) group; the protein intake goals (g/kgw/day) were 1.5 for IC and 1.0 for SC. There was a significant improvement in grip strength only in the IC group (1.1 kg: 95% CI 0.1 to 2.1) (p = 0.02). While the skeletal muscle index and ADL indices were not significantly improved in either group, the improvement ratio tended to be greater in the IC group. There was no decrease in renal function in either group. Thus, intervention of increased dietary protein in daily-life settings for 6 months in adults aged 75 or older with treatable cancer, pneumonia, fractures, and/or urinary-tract infection and at nutritional risk may be effective in ameliorating loss of muscle strength.

Inhibition of GIP signaling extends lifespan without caloric restriction.

AIMS/INTRODUCTION: Caloric restriction (CR) promotes longevity and exerts anti-aging effects by increasing Sirtuin production and activation. Gastric inhibitory polypeptide (GIP), a gastrointestinal peptide hormone, exerts various effects on pancreatic ß-cells and extra-pancreatic tissues. GIP promotes glucose-dependent augmentation of insulin secretion and uptake of nutrients into the adipose tissue. MATERIALS AND METHODS: Gipr-/- and Gipr+/+ mice were used for lifespan analysis, behavior experiments and gene expression of adipose tissue and muscles. 3T3-L1 differentiated adipocytes were used for Sirt1 and Nampt expression followed by treatment with GIP and α-lipoic acid. RESULTS: We observed that GIP receptor-knockout (Gipr-/-) mice fed normal diet showed an extended lifespan, increased exploratory and decreased anxiety-based behaviors, which are characteristic behavioral changes under CR. Moreover, Gipr-/- mice showed increased Sirt1 and Nampt expression in the adipose tissue. GIP suppressed α-lipoic acid-induced Sirt1 expression and activity in differentiated adipocytes. CONCLUSIONS: Although maintenance of CR is difficult, food intake and muscle endurance of Gipr-/- mice were similar to those of wild-type mice. Inhibition of GIP signaling may be a novel strategy to extend the lifespan of diabetic patients.

Food Intake Affects Sperm-Egg Fusion Through the GIP/PSG17 Axis in Mice.

In addition to overeating, starvation also reduces fecundity in mammals. However, little is known about the molecular mechanisms linking food intake to fertility, especially in males. Gastric inhibitory polypeptide (GIP), which is released from intestinal K-cells after meal ingestion, stimulates insulin secretion from pancreatic ß-cells through the action of incretin and has several extrapancreatic effects. Here, we identified GIP receptor (Gipr) expression in mouse spermatids. Microarray analysis revealed that pregnancy-specific glycoprotein 17 (Psg17), a potential CD9-binding partner, was significantly decreased in GIP receptor-knockout (Gipr-/-) testes. Glycosylphosphatidylinositol-anchored PSG17 was expressed on the surface of acrosome-reacted sperm, and Gipr-/- sperm led to a lower fertilization rate in vitro, compared with that of Gipr+/+ sperm, both in the absence and presence of the zona pellucida. Plasma GIP concentrations and Psg17 messenger RNA (mRNA) were immediately increased in the testis after a single meal, whereas ingestion of a chronic high-fat diet markedly decreased Gipr and Psg17 mRNA. These results suggest that reduced GIP signaling, by decreased GIP levels or the downregulation of Gipr, is associated with the reduction of fecundity due to starvation or overeating. Thus, proper regulation of GIP signaling in the testis could be a potential unique therapeutic target for male infertility in obese and diabetic individuals.

Stromal cell-derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy.

The role of stromal cell-derived factor-1 (SDF-1) in the pathogenesis of diabetic nephropathy and its modification by dipeptidyl peptidase-4 (DPP-4) inhibition are uncertain. Therefore, we studied this independent of glucagon-like peptide-1 receptor (GLP-1R) signaling using two Akita diabetic mouse models, the diabetic-resistant C57BL/6-Akita and diabetic-prone KK/Ta-Akita. Increased SDF-1 expression was found in glomerular podocytes and distal nephrons in the diabetic-prone mice, but not in kidneys from diabetic-resistant mice. The DPP-4 inhibitor linagliptin, but not the GLP-1R agonist liraglutide, further augmented renal SDF-1 expression in both Glp1r(+/+) and Glp1r(-/-) diabetic-prone mice. Along with upregulation of renal SDF-1 expression, the progression of albuminuria, glomerulosclerosis, periglomerular fibrosis, podocyte loss, and renal oxidative stress was suppressed in linagliptin-treated Glp1r(+/+) diabetic-prone mice. Linagliptin treatment increased urinary sodium excretion and attenuated the increase in glomerular filtration rate which reflects glomerular hypertension and hyperfiltration. In contrast, selective SDF-1 receptor blockade with AMD3100 reduced urinary sodium excretion and aggravated glomerular hypertension in the Glp1r(+/+) diabetic-prone mice. Thus, DPP-4 inhibition, independent of GLP-1R signaling, contributes to protection of the diabetic kidney through SDF-1-dependent antioxidative and antifibrotic effects and amelioration of adverse renal hemodynamics.

Anti-inflammatory role of glucose-dependent insulinotropic polypeptide in periodontitis.

AIMS/INTRODUCTION: The involvement of glucose-dependent insulinotropic polypeptide (GIP) on inflammation was explored in atherosclerosis and adipose tissue. Periodontal disease is a chronic inflammatory disease, and is considered one of the diabetic complications. In the present study, to examine the effect of GIP on periodontitis, we induced experimental periodontitis in glucose-dependent insulinotropic polypeptide receptor-knockout mice (GIPRKO). We also investigated the anti-inflammatory effect of GIP in a culture system. MATERIALS AND METHODS: Experimental periodontitis was induced by ligature wire in GIPRKO and C57BL/C mice. Two weeks after the ligature, immunohistological evaluation and inflammatory messenger ribonucleic acid expression in the gingiva was examined. To elucidate the role of GIP in inflammation, the effects of GIP on lipopolysaccharide-induced gene expressions in THP-1 cells were evaluated. RESULTS: Periodontitis increased inflammatory cell infiltration, macrophage accumulation and tumor necrosis factor-α and nitric oxide synthase gene expressions in the gingiva. Periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue. Mac-1-positive macrophages and the inflammatory gene expressions were significantly increased in periodontitis in GIPRKO compared with C57BL/C mice periodontitis. Immunohistochemical staining confirmed that GIP receptors were expressed in residual and infiltrated Mac-1-positive macrophages. The in vitro study showed that GIP suppressed lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide synthase gene expression in a dose-dependent manner. Furthermore, the inhibitory effect of GIP on lipopolysaccharide-induced inflammatory gene expressions was at least partially through cyclic adenosine monophosphate/protein kinase A pathway. CONCLUSIONS: These results suggest the beneficial effects of GIP on periodontal disease. In diabetic patients, GIP is expected to have a direct anti-inflammatory effect on periodontitis in addition to its glucose-lowering effect.

Novel extrapancreatic effects of incretin.

The hormonal factors implicated as transmitters of signals from the gut to pancreatic ß-cells are referred to as incretins. Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretins. In addition to the insulinotropic effects, we have shown, using the GIP receptor and GLP-1 receptor-deficient mice, that GIP and GLP-1 have direct actions on adipocytes and the kidney, respectively. Because GIP receptors and GLP-1 receptors are differentially expressed in a tissue-specific manner, GIP and GLP-1 have specific physiological activities, and further comprehensive characterization of the extrapancreatic actions of GIP and GLP-1 is anticipated, as dipeptidyl peptidase IV inhibitors activate both GIP and GLP-1 signaling.

Effects of miglitol, sitagliptin, and initial combination therapy with both on plasma incretin responses to a mixed meal and visceral fat in over-weight Japanese patients with type 2 diabetes. "the MASTER randomized, controlled trial".

AIM: To assess changes in circulating incretin levels and body fat compositions with initial combination therapy with α-glucosidase inhibitor and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes (T2D). METHODS: In this multicenter open-label 24-week trial, Japanese over-weight (BMI ≥ 25 kg/m(2)) patients with T2D not taking medication or taking metformin and/or sulfonylurea were randomly assigned to receive either 50mg of miglitol three times a day (M, n=14), 50mg of sitagliptin once a day (S, n=14), or a combination of both (M+S, n=13). Changes in plasma incretin levels during a meal tolerance test (MTT) and body fat composition with impedance method were evaluated. RESULTS: During MTT, postprandial plasma glucose levels decreased more after M+S than after M or S, and postprandial serum insulin levels decreased significantly after M and M+S whereas they increased after S. After M, active gastric inhibitory polypeptide (aGIP) decreased significantly at 30 min despite a significant increase at 120 min. After S, aGIP levels increased significantly throughout the MTT. After M+S, aGIP increased significantly at 0 and 120 min despite of significant decrease at 30 min. M+S further enhanced postprandial active glucagon-like peptide-1 levels during MTT than S did. Total body fat mass decreased significantly after M and M+S. Visceral fat mass decreased significantly only after M+S. Serum adiponectin increased significantly only after M+S. CONCLUSIONS: In over-weight patients with T2D, M+S may have a beneficial effect on adiposity with relation to these different effects on two incretins.

The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential.

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy-resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P)H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P)H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation.

The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice.

Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic ß cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [(14)C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [(14)C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin-mediated pathway rather than through a GLP-1-mediated pathway.

Glycemic instability in type 1 diabetic patients: Possible role of ketosis or ketoacidosis at onset of diabetes.

AIMS: In type 1 diabetic patients, some have glycemic instability while others glycemic stability. We have developed criteria for evaluating glycemic instability and investigated the factors responsible. METHODS: Glycemic instability in 52 type 1 diabetic patients was assessed by the mean amplitude of glycemic excursions (MAGE) and M-value, and clinical characteristics of good, fair and poor control groups were compared. RESULTS: The median MAGE and M-value was 6.6mmol/L and 18.7, respectively. Then MAGE >or=6.6mmol/L and M-value >or=18.7 was defined as poor control. In the 32 patients without detectable C-peptide levels, 18 patients (56%) showed poor control. The frequency of ketosis or ketoacidosis at onset of diabetes was dramatically higher in the poor control group not only in the patients as a whole but also in those without detectable C-peptide levels. CONCLUSIONS: A decreased level of C-peptide is a significant factor in glycemic instability. However, some patients have glycemic stability though beta-cell function is completely depleted. The presence of ketosis or ketoacidosis at onset of diabetes may be a factor in later glycemic instability, suggesting the importance of examining patients in detail at onset of diabetes for careful follow-up to prevent progression of acute and chronic complications of diabetes.

The murine glucagon-like peptide-1 receptor is essential for control of bone resorption.

Gastrointestinal hormones including gastric inhibitory polypeptide (GIP), glucagon-like peptide (GLP)-1, and GLP-2 are secreted immediately after meal ingestion, and GIP and GLP-2 have been shown to regulate bone turnover. We hypothesize that endogenous GLP-1 may also be important for control of skeletal homeostasis. We investigated the role of GLP-1 in the regulation of bone metabolism using GLP-1 receptor knockout (Glp-1r(-/-)) mice. A combination of bone density and histomorphometry, osteoclast activation studies, biochemical analysis of calcium and PTH, and RNA analysis was used to characterize bone and mineral homeostasis in Glp-1r(-/-) and Glp-1r(+/+) littermate controls. Glp-1r(-/-) mice have cortical osteopenia and bone fragility by bone densitometry as well as increased osteoclastic numbers and bone resorption activity by bone histomorphometry. Although GLP-1 had no direct effect on osteoclasts and osteoblasts, Glp-1r(-/-) mice exhibited higher levels of urinary deoxypyridinoline, a marker of bone resorption, and reduced levels of calcitonin mRNA transcripts in the thyroid. Moreover, calcitonin treatment effectively suppressed urinary levels of deoxypyridinoline in Glp-1r(-/-), mice and the GLP-1 receptor agonist exendin-4 increased calcitonin gene expression in the thyroid of wild-type mice. These findings establish an essential role for endogenous GLP-1 receptor signaling in the control of bone resorption, likely through a calcitonin-dependent pathway.

A novel GIP receptor splice variant influences GIP sensitivity of pancreatic beta-cells in obese mice.

Gastric inhibitory polypeptide (GIP) is an incretin that potentiates insulin secretion from pancreatic beta-cells by binding to GIP receptor (GIPR) and subsequently increasing the level of intracellular adenosine 3',5'-cyclic monophosphate (cAMP). We have identified a novel GIPR splice variant in mouse beta-cells that retains intron 8, resulting in a COOH-terminal truncated form (truncated GIPR). This isoform was coexpressed with full-length GIPR (wild-type GIPR) in normal GIPR-expressing tissues. In an experiment using cells transfected with both GIPRs, truncated GIPR did not lead to cAMP production induced by GIP but inhibited GIP-induced cAMP production through wild-type GIPR (n = 3-4, P < 0.05). Wild-type GIPR was normally located on the cell surface, but its expression was decreased in the presence of truncated GIPR, suggesting a dominant negative effect of truncated GIPR against wild-type GIPR. The functional relevance of truncated GIPR in vivo was investigated. In high-fat diet-fed obese mice (HFD mice), blood glucose levels were maintained by compensatory increased insulin secretion (n = 8, P < 0.05), and cAMP production (n = 6, P < 0.01) and insulin secretion (n = 10, P < 0.05) induced by GIP were significantly increased in isolated islets, suggesting hypersensitivity of the GIPR. Total GIPR mRNA expression was not increased in the islets of HFD mice, but the expression ratio of truncated GIPR to total GIPR was reduced by 32% compared with that of control mice (n = 6, P < 0.05). These results indicate that a relative reduction of truncated GIPR expression may be involved in hypersensitivity of GIPR and hyperinsulinemia in diet-induced obese mice.

Genetic inactivation of GIP signaling reverses aging-associated insulin resistance through body composition changes.

Aging is associated with increased fat mass and decreased lean mass, which is strongly associated with the development of insulin resistance. Gastric inhibitory polypeptide (GIP) is known to promote efficient storage of ingested nutrients into adipose tissue; we examined aging-associated changes in body composition using 10-week-old and 50-week-old wild-type (WT) and GIP receptor knockout (Gipr-/-) mice on a normal diet, which show no difference in body weight. We found that Gipr-/- mice showed significantly reduced fat mass without reduction of lean mass or food intake, while WT mice showed increased fat mass and decreased lean mass associated with aging. Moreover, aged Gipr-/- mice showed improved insulin sensitivity, which is associated with amelioration in glucose tolerance, higher plasma adiponectin levels, and increased spontaneous physical activity. We therefore conclude that genetic inactivation of GIP signaling can prevent the development of aging-associated insulin resistance through body composition changes.

Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) control glucose homeostasis through well-defined actions on the islet beta cell via stimulation of insulin secretion and preservation and expansion of beta cell mass. We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r(-/-), Gipr(-/-), and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor-1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist [D-Ala(2)]GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the beta cell via control of adipokine secretion and energy expenditure.

Living donor islet transplantation, the alternative approach to overcome the obstacles limiting transplant.

We performed the world's first successful living donor islet transplantation for unstable diabetes. A total of 408,114 islet equivalents were isolated from half a living pancreas and transplanted immediately to the recipient who was a 27-year-old female. The donor was a 56-year-old female in good health, mother of the recipient. The islets functioned immediately, and the recipient was weaned completely from insulin on the 22nd posttransplant day, and has maintained excellent glycemic control since. The donor was discharged on the 18th postoperative day with normal oral glucose tolerance test and without complications. Living donor islet transplantation could cure one insulin-dependent diabetes mellitus patients with a single donor. There are some advantages in the living donor islet transplantation: (a) living donor can alleviate the issue of donor shortage; (b) highly potent islets can be isolated from a living donor; and (c) the recipient can be treated with immunosuppressant and controlled blood glucose level tightly prior to the transplantation. These are important factors in overcoming the obstacles limiting islet transplantation. We believe that the living donor islet transplantation may become an additional option in treating insulin-dependent diabetes.

SUIT, secretory units of islets in transplantation: An index for therapeutic management of islet transplanted patients and its application to type 2 diabetes.

Evaluation of a patient's pancreatic beta-cell function is important in both diagnosis and treatment of diabetes. We sought to determine beta-cell function with a single sampling of blood. Examination of fasting blood glucose (F-BG, mM) and C-peptide (F-CPR, nM) levels in seven post-islet-transplanted states of four patients revealed a linear relationship between F-BG and F-CPR. Assuming that normal subjects aged <40 years have 100% pancreatic beta-cell function, we developed the secretory units of islets in transplantation (SUIT) as an index of beta-cell function by the formula: 250 x F-CPR/(F-BG-3.43). The SUIT index was correlated with the stimulated C-peptide levels not only in islet-transplanted patients (R2 = 0.68, P < 0.05) but also in type 2 patients (R2 = 0.34, P < 0.001). Since the SUIT index can be calculated from data obtained at a single fasting blood sampling and predict the pancreatic beta-cell function, the formula may be a useful tool in clinical management of diabetes.

Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion.

Calcium plays a fundamental role as second messenger in intracellular signaling and bone serves as the body's calcium reserve to tightly maintain blood calcium levels. Calcium in ingested meal is the main supply and inadequate calcium intake causes osteoporosis and bone fracture. Here, we describe a novel mechanism of how ingested calcium is deposited on bone. Meal ingestion elicits secretion of the gut hormone gastric inhibitory polypeptide (GIP) from endocrine K cells in the duodenum. Bone histomorphometrical analyses revealed that bone formation parameters in the mice lacking GIP receptor (GIPR(-/-)) were significantly lower than those of wild-type (GIPR(+/+)) mice, and that the number of osteoclasts, especially multinuclear osteoclasts, was significantly increased in GIPR(-/-) mice, indicating that GIPR(-/-) mice have high-turnover osteoporosis. In vitro examination showed the percentage of osteoblastic cells undergoing apoptosis to be significantly decreased in the presence of GIP. Because GIPR(-/-) mice exhibited an increased plasma calcium concentration after meal ingestion, GIP directly links calcium contained in meal to calcium deposition on bone.

Gastric inhibitory polypeptide modulates adiposity and fat oxidation under diminished insulin action.

Gut hormone gastric inhibitory polypeptide (GIP) stimulates insulin secretion from pancreatic beta-cells upon ingestion of nutrients. Inhibition of GIP signaling prevents the onset of obesity and consequent insulin resistance induced by high-fat diet. In this study, we investigated the role of GIP in accumulation of triglycerides into adipocytes and in fat oxidation peripherally using insulin receptor substrate (IRS)-1-deficient mice and revealed that IRS-1(-/-)GIPR(-/-) mice exhibited both reduced adiposity and ameliorated insulin resistance. Furthermore, increased gene expression of CD36 and UCP2 in liver, and increased expression and enzyme activity of 3-hydroxyacyl-CoA dehydrogenase in skeletal muscle of IRS-1(-/-)GIPR(-/-) mice might contribute to the lower respiratory quotient and the higher fat oxidation in light phase. These results suggest that GIP plays a crucial role in switching from fat oxidation to fat accumulation under the diminished insulin action as a potential target for secondary prevention of insulin resistance.

Insulin independence after living-donor distal pancreatectomy and islet allotransplantation.

Rising demand for islet transplantation will lead to severe donor shortage in the near future, especially in countries where cadaveric organ donation is scarce. We undertook a successful transplantation of living-donor islets for unstable diabetes. The recipient was a 27-year-old woman who had had brittle, insulin-dependent diabetes mellitus for 12 years. The donor, who was a healthy 56-year-old woman and mother of the recipient, underwent a distal pancreatectomy. After isolation, 408 114 islet equivalents were transplanted immediately. The transplants functioned immediately and the recipient became insulin-independent 22 days after the operation. The donor had no complications and both women showed healthy glucose tolerance. Transplantation of living-donor islets from the distal pancreas can be sufficient to reverse brittle diabetes.