Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on β cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater β cell mass secondary to increased β cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 β cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes. IntroductionThe factors that promote β cell failure and increase the incidence of diabetes in obese individuals are not fully understood. The presence of hyperglycemia and hyperphagia in obese individuals, despite the presence of high levels of circulating insulin and leptin, suggests these individuals are resistant to the actions of both hormones (1). The hypothalamic actions of leptin are relatively well characterized; however, the expression of the long form of the leptin receptor (ObRb) in peripheral tissues, including the endocrine pancreas, indicates that leptin can also exert peripheral actions independent of its effects in the hypothalamus (2). For example, in vitro studies have reported inhibitory effects of leptin on insulin gene expression and insulin secretion in β cell lines and isolated murine and human islets (2-4). Furthermore, leptin treatment of ob/ob mice reversed hyperinsulinemia (5). Although the db/db mouse, which carries a mutation in the ObR gene (6), manifests hyperinsulinemia and hyperplastic islets (7), it is unclear whether the alterations in islet growth and function in db/db mice are due to a lack of direct leptin action in β cells or secondary to the effects of insulin resistance in peripheral tissues.To directly assess the role of leptin signaling in the pancreas, we used the Cre-loxP technique to create a mouse model that is

OBJECTIVE -To investigate the impact of glycemic control on the survival of diabetic subjects with end-stage renal disease (ESRD) starting hemodialysis treatment. RESEARCH DESIGN AND METHODS-This single-center prospective observational study enrolled 150 diabetic ESRD subjects (109 men and 41 women; age at hemodialysis initiation, 60.5 Ϯ 10.2 years) at start of hemodialysis between January 1989 and December 1997. The subjects were divided into groups according to their glycemic control level at inclusion as follows: good HbA 1c Ͻ7.5%, n ϭ 93 (group G), and poor HbA 1c Ն7.5%, n ϭ 57 (group P); and survival was followed until December 1999, with a mean follow-up period of 2.7 years.RESULTS -Group G had better survival than group P (the control group) (P ϭ 0.008). At inclusion, there was no significant difference in age, sex, systolic blood pressure (SBP), BMI, cardio-to-thoracic ratio (CTR) on chest X-ray, and serum creatinine (Cre) or hemoglobin (Hb) levels between the two groups. After adjustment for age and sex, HbA 1c was a significant predictor of survival (hazard ratio 1.133 per 1.0% increment of HbA 1c , 95% CI 1.028 -1.249, P ϭ 0.012), as were Cre and CTR.CONCLUSIONS -Good glycemic control (HbA 1c Ͻ7.5%) predicts better survival of diabetic ESRD patients starting hemodialysis treatment. Diabetes Care 24:909 -913, 2001

OBJECTIVE -To investigate whether the quantitative insulin sensitivity check index (QUICKI) and the reciprocal index of homeostasis model assessment (1/HOMA-IR) derived from fasting plasma glucose and insulin level are excellent surrogate indices of insulin resistance in both normal range-weight and moderately obese type 2 diabetic and healthy subjects. RESEARCH DESIGN AND METHODS -The association between QUICKI or 1/HOMA-IR and insulin resistance index assessed by euglycemic-hyperinsulinemic clamp (clamp-IR) was investigated in 121 type 2 diabetic and 29 healthy subjects recruited from among 120 (age 55 Ϯ 11, 48 Ϯ 15, and 52 Ϯ 15 years [means Ϯ SD], respectively). Type 2 diabetic subjects were divided into groups of 76 normal range-weight and 45 moderately obese subjects (BMI 21.4 Ϯ 2.3 vs. 27.2 Ϯ 2.2 kg/m 2 , P Ͻ 0.0001).RESULTS -QUICKI and 1/HOMA-IR were significantly lower in the moderately obese group than in the normal range-weight type 2 diabetic and healthy groups (n ϭ 120) (QUICKI, 0.338 Ϯ 0.030, 0.371 Ϯ 0.037, and 0.389 Ϯ 0.041, respectively, P Ͻ 0.0001; 1/HOMA-IR, 0.50 Ϯ 0.33, 0.92 Ϯ 0.55, and 1.24 Ϯ 0.82, P Ͻ 0.0001). QUICKI was strongly correlated with clamp-IR in normal range-weight, moderately obese type 2 diabetic, and healthy subjects (r ϭ 0.641, 0.570, and 0.502, respectively; all subjects, r ϭ 0.608, P Ͻ 0.01) and 1/HOMA-IR exhibited correlations comparable to those of QUICKI with clamp-IR (r ϭ 0.637, 0.530, and 0.461, respectively; all subjects, r ϭ 0.589, P Ͻ 0.001). In multiple regression models including QUICKI or 1/HOMA-IR as an independent variable, the estimation formula accounted for 55% of the variability of clamp-IR for the group of all type 2 diabetic subjects (R 2 ϭ 0.547 and 0.551, respectively, P Յ 0.0001).CONCLUSIONS -QUICKI and 1/HOMA-IR were highly correlated with clamp-IR, with comparable coefficients in both normal range-weight and moderately obese type 2 diabetic patients and nondiabetic subjects. The latter can probably be applied clinically in view of its convenience. Diabetes Care 26:2426 -2432, 2003I nsulin resistance might play an important role in hyperglycemia in type 2 diabetes, which eventually induces the development of diabetic microangiopathy (1). To achieve excellent glycemic control to prevent these complications, several oral hypoglycemic agents (OHAs) that improve insulin resistance (such as thiazolidinediones and biguanides) have been developed and are available clinically (2,3). Furthermore, insulin resistance is proposed to play important roles in the pathogenesis of cardiovascular diseases (4), the most common cause of death in diabetic patients. Therefore, it is important clinically and epidemiologically to evaluate insulin resistance simply and accurately in individual diabetic patients.The euglycemic-hyperinsulinemic clamp, the gold standard technique for estimation of insulin resistance, is accurate but complex and laborious enough that it is not practical for evaluation of a large number of type 2 diabetic patients or populations at risk for insulin...

OBJECTIVE—To investigate the impact of glycemic control during regular hemodialysis on the survival of diabetic patients with chronic kidney disease (CKD) in a longitudinal observational study. RESEARCH DESIGN AND METHODS—A total of 114 diabetic CKD patients on hemodialysis at Inoue Hospital (Suita, Japan) were surveyed from May 1995 to December 2002 (survey period 45.5 ± 29.3 [means ± SD] months). All subjects were categorized into three groups by mean HbA1c (A1C) level during the 3-month period on hemodialysis preceding entry, as follows: good (A1C <6.5%, 5.7 ± 0.4%, n = 34), fair (6.5 ≤ A1C < 8.0%, 7.2 ± 0.4%, n = 39), and poor (A1C ≥8.0%, 9.2 ± 0.9%, n = 41) A1C groups. RESULTS—There were no significant differences in age at entry, initiation of hemodialysis, duration of hemodialysis, blood pressure, cardiothoracic ratio, serum creatinine level, or hemoglobin level among the three groups. The cumulative survival of the poor A1C group during the survey was significantly lower than that of the fair and good A1C groups as determined by Kaplan-Meier estimation (P = 0.041, log-rank test). In a multivariate Cox proportional hazard model, both poor A1C group (hazard ratio 2.889, P = 0.010) and mean A1C (1.260 per 1.0%, P = 0.003) were significant predictors of survival. CONCLUSIONS—In diabetic CKD patients on regular hemodialysis, poor glycemic control is an independent predictor of prognosis. This finding indicates the importance of careful management of glycemic control even after initiation of hemodialysis.

Angiogenic response is impaired in diabetes. Here, we examined the involvement of receptor for advanced glycation end products (RAGE) in diabetes-related impairment of angiogenesis in vivo. Angiogenesis was determined in reconstituted basement membrane protein (matrigel) plugs containing vascular endothelial growth factor (VEGF) implanted into nondiabetic or insulin-deficient diabetic wild-type or RAGE ؊/؊ mice. The total, endothelial, and smooth muscle (or pericytes) cells in the matrigel were significantly decreased in diabetes, with the regulation dependent on RAGE. In the matrigel, proangiogenic VEGF expression was decreased, while antiangiogenic thrombospondin-1 was upregulated in diabetic mice, regardless of the presence of RAGE. In wild-type mice, proliferating cell nuclear antigen (PCNA)-positive cells in the matrigel were significantly less in diabetic than in nondiabetic mice, while the numbers of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells were significantly higher. This alteration in PCNA-and TUNEL-positive cells in diabetes was not observed in RAGE ؊/؊ mice. Similarly, the percentage of nuclear factor B-activated cells is enhanced in diabetes, with the regulation dependent on the presence of RAGE. Importantly, adenovirus-mediated overexpression of endogenous secretory RAGE, a decoy receptor for RAGE, restores diabetes-associated impairment of angiogenic response in vivo. Thus, RAGE appears to be involved in impairment of angiogenesis in diabetes, and blockade of RAGE might be a potential therapeutic target. Diabetes 55: [2245][2246][2247][2248][2249][2250][2251][2252][2253][2254][2255] 2006