A randomized clinical trial of basal insulin peglispro vs NPH in insulin-naïve patients with type 2 diabetes: the IMAGINE 6 trial.

AIMS: Basal insulin peglispro (BIL) has a longer duration of action than conventional insulin analogues and a hepato-preferential mechanism of action. This study assessed whether BIL was non-inferior to isophane insulin (NPH) in reducing HbA1c in insulin-naïve patients with type 2 diabetes, when added to pre-study oral anti-hyperglycaemic medications. MATERIALS AND METHODS: This was a Phase 3, open-label, treat-to-target (TTT), randomized trial with a 2-week lead-in, 26-week treatment and a 4-week safety follow-up period. Patients were randomized to bedtime (pm) NPH, morning (am) BIL or pm BIL in a 1:1:1 ratio. RESULTS: Six hundred and forty-one patients [NPH, n = 213; BIL, n = 428 (am, n = 213; pm, n = 215)] received study drug. BIL was non-inferior to NPH for HbA1c change from baseline at Week 26 with a between-treatment difference (95% confidence interval) of -0.37% (-0.50, -0.23%). HbA1c at baseline was 8.5%, and was lower in BIL- vs NPH-treated patients after 26 weeks of treatment (6.8% vs 7.1%; P < .001). More BIL-treated patients achieved HbA1c <7.0% and HbA1c <7.0% without nocturnal hypoglycaemia. Fasting serum glucose levels and nocturnal hypoglycaemia rates were lower in BIL-treated patients; total hypoglycaemia rates were similar. Treatment-emergent adverse events were similar between groups. Fasting triglycerides decreased from baseline in both groups and to a greater extent with NPH, but were not significantly different between groups at Week 26. Mean alanine aminotransferase (ALT) increased with BIL treatment, but there was no evidence of acute severe hepatotoxicity. CONCLUSIONS: In this TTT study, BIL treatment showed clinically relevant improvements in glycaemic control and a significant reduction in nocturnal hypoglycaemia compared to NPH.

Early fasting glucose measurements can predict later glycaemic response to once weekly dulaglutide.

AIMS: To assess whether early measures of fasting blood glucose predict later glycaemic response with once-weekly dulaglutide in patients with Type 2 diabetes mellitus. METHODS: Post hoc analyses were conducted separately for two phase 3 studies (AWARD-5 and AWARD-1) in patients assigned to once-weekly dulaglutide. Week 2 fasting blood glucose was used as a predictor variable, and glycaemic treatment response was defined by HbA1c response based on a composite efficacy endpoint. The association between fasting blood glucose and the glycaemic response was analysed using chi-square tests. RESULTS: There was a strong association between fasting blood glucose < 7.9 mmol/l at week 2 and achieving the HbA1c composite efficacy endpoint at week 26 (P < 0.01). Higher fasting blood glucose at week 2, however, did not predict absence of glycaemic response and requires further assessment. CONCLUSIONS: Fasting blood glucose measured at 2 weeks may be an early and useful predictor of glycaemic response to once-weekly dulaglutide treatment.

The need for better insulin therapy.

Insulin replacement therapy corrects a core defect of diabetes pathophysiology. Since its introduction as a therapeutic modality almost 100 years ago, insulin therapy has undergone remarkable changes in purity and ability to provide more physiologic control of blood glucose levels. With glucose-lowering potential limited only by risks of hypoglycaemia, which remains the major limitation in our ability to achieve glycaemic goals, insulin replacement therapy remains a cornerstone of therapy. Major progress in reducing the risks of hypoglycemia has occurred with the development of insulin analogs. This review article briefly chronicles the evolution of insulin replacement strategies, highlighting both challenges in pharmaceutical development and patient acceptance, underscoring achievements, as well as denoting what improvements are still needed.

Monotherapy with the once-weekly GLP-1 analogue dulaglutide for 12 weeks in patients with Type 2 diabetes: dose-dependent effects on glycaemic control in a randomized, double-blind, placebo-controlled study.

AIMS: Evaluate dose-dependent effects of once-weekly dulaglutide, a glucagon-like peptide-1 analogue, on glycaemic control in patients with Type 2 diabetes treated with lifestyle measures with or without previous metformin. METHODS: This 12-week, double-blind, placebo-controlled, dose-response trial randomized 167 patients who were anti-hyperglycaemic medication-naïve or had discontinued metformin monotherapy [mean baseline HbA(1c) 59 ± 8 to 61 ± 8 mmol/mol (7.6 ± 0.7 to 7.8 ± 0.8%)] to once-weekly injections of placebo or dulaglutide (0.1, 0.5, 1.0 or 1.5 mg). RESULTS: A significant dose-dependent reduction in HbA(1c) (least squares mean ± SE) was observed across doses (P < 0.001). HbA(1c) reductions in the 0.5, 1.0 and 1.5 mg dulaglutide groups were greater than in the placebo group [-10 ± 1, -11 ± 1 and -11 ± 1 vs. 0 ± 1 mmol/mol (-0.9 ± 0.1, -1.0 ± 0.1 and -1.0 ± 0.1 vs. 0.0 ± 0.1%), respectively, all P < 0.001]. Dose-dependent reductions in fasting plasma glucose were also observed [least squares mean difference (95% CI) ranging from -0.43 (-1.06 to 0.19) mmol/l for dulaglutide 0.1 mg to -1.87 (-2.56 to -1.19) mmol/l for dulaglutide 1.5 mg, P < 0.001]. Dose-dependent weight loss was demonstrated across doses (P = 0.009), but none of the groups were different from placebo. The most common adverse events were nausea and diarrhoea. CONCLUSIONS: The observed dulaglutide dose-dependent reduction in HbA(1c) and its acceptable safety profile support further clinical development for treatment of Type 2 diabetes.

Molecular basis for the insulinomimetic effects of C-peptide.

AIMS/HYPOTHESIS: C-peptide, released by the beta-cells of pancreatic islets, elicits salutary responses in Type I (insulin-dependent) diabetes mellitus but the molecular mechanisms behind these effects are not known. We assessed whether synthetic rat C-peptide stimulates insulin-like cellular effects in a classic insulin target tissue. METHODS: To clarify the molecular mechanisms involved in several insulinomimetic actions, we investigated the effect of C-peptide on the insulin signalling pathway in rat skeletal muscle cells. We used L6 myoblasts and myocytes to measure the effects of C-peptide or insulin or both on glycogen synthesis and amino acid uptake. We also studied the effects of C-peptide on insulin receptor autophosphorylation, its tyrosine kinase activity, phosphorylation of IRS-1, PI 3-kinase, Akt, p90Rsk, MAPK, and GSK3 in these cells. RESULTS: In L6 cells, physiological concentrations of C-peptide (0.3-3 nmol/l) significantly activated insulin receptor tyrosine kinase, IRS-1 tyrosine phosphorylation, PI 3-kinase activity, MAPK phosphorylation, p90Rsk, and GSK3 phosphorylation. A scrambled C-peptide sequence - the control - showed no effects. Wortmannin blocked C-peptide-induced glycogen synthesis while pertussis toxin had no effect. Only submaximal insulin concentrations (up to 10 nmol/l) combined with submaximal C-peptide concentrations led to additive effects. CONCLUSION/INTERPRETATION: C-peptide added to the maximal insulin dose (100 nmol/l) did not increase the effect of insulin alone. We thus conclude that the same signalling elements are used by both ligands. However, the lack of Akt activation by C-peptide and the bell-shaped dose response induced by C-peptide indicate that C-peptide has some effects by another distinct mechanism. We speculate that C-peptide could modulate the metabolic effects of insulin by enhancing them at low hormone concentrations and dampening them at high hormone concentrations.

C-peptide prevents and improves chronic Type I diabetic polyneuropathy in the BB/Wor rat.

AIMS/HYPOTHESIS: Insulin and C-peptide exert neuroprotective effects and are deficient in Type I (insulin-dependent) diabetes mellitus but not in Type II (non-insulin-dependent) diabetes mellitus. These studies were designed to test the preventive and interventional effects of C-peptide replacement on diabetic polyneuropathy in the Type I diabetic BB/Wor rat. METHODS: Diabetic BB/Wor rats were replaced with rat C-peptide from onset of diabetes and between 5 and 8 months of diabetes. They were examined at 2 and 8 months and compared to non-C-peptide replaced BB/Wor rats, Type II diabetic (non-C-peptide deficient) BB/Z rats and non-diabetic control rats. Animals were monitored as to hyperglycaemia and nerve conduction velocity (NCV). Acute changes such as neural Na+/K+-ATPase and paranodal swelling were examined at 2 months, morphometric and teased fiber analyses were done at 8 months. RESULTS: C-peptide replacement for 2 months in Type I diabetic rats prevented the acute NCV defect by 59% (p < 0.005), the neural Na+/K+-ATPase defect by 55% (p < 0.001) and acute paranodal swelling by 61% (p < 0.001). Eight months of C-peptide replacement prevented the chronic nerve conduction defect by 71% (p < 0.001) and totally prevented axoglial dysjunction (p < 0.001) and paranodal demyelination (p < 0.001). C-peptide treatment from 5 to 8 months showed a 13% (p < 0.05) improvement in NCV, a 33% (p < 0.05) improvement in axoglial dysjunction, normalization (p < 0.001) of paranodal demyelination, repair of axonal degeneration (p < 0.01), and a fourfold (p < 0.001) increase in nerve fibre regeneration. CONCLUSION/INTERPRETATION: C-peptide replacement of Type I BB/Wor-rats partially prevents acute and chronic metabolic, functional and structural changes that separate Type I diabetic polyneuropathy from its Type II counterpart suggesting that C-peptide deficiency plays a pathogenetic role in Type I diabetic polyneuropathy.

Genetic mapping and functional studies of a natural inhibitor of the insulin receptor tyrosine kinase: the mouse ortholog of human alpha2-HS glycoprotein.

Fetuin/alpha2-HS glycoprotein (alpha2-HSG) homologs have been identified in several species including rat, sheep, pig, rabbit, guinea pig, cattle, mouse and human. Multiple physiological roles for these homologs have been suggested, including ability to bind to hydroxyapatite crystals and to specifically inhibit the tyrosine kinase (TK) activity of the insulin receptor (IR). In this study we report the identification, cloning, and characterization of the mouse Ahsg gene and its function as an IR-TK inhibitor. Genomic clones derived from a mouse Svj 129 genomic library were sequenced in order to characterize the intron-exon organization of the mouse Ahsg gene, including an 875 bp subclone containing 154 bp upstream from the transcription start site, the first exon, and part of the first intron. A second genomic subclone harboring a 3.45 kb Bgl II fragment contained exons 2, 3 and 4 in addition to two adjacent elements within the first intron-a repetitive element of the B1 family (92 bp) and a 271 bp tract of (T,C)n*(A,G)n. We have mapped mouse Ahsg at 16 cM adjacent to the Diacylglycerol kinase 3 (Dagk3) gene on chromosome 16 by genotyping interspecific backcross panels between C57BL/6J and Mus spretus. The position is syntenic with human chromosome 3q27, where the human AHSG gene resides. Using recombinant mouse alpha2-HSG expressed from a recombinant baculovirus, we demonstrate that mouse alpha2-HSG inhibits insulin-stimulated IR autophosphorylation and IR-TKA in vitro. In addition, mouse alpha2-HSG (25 microg/ml) completely abolishes insulin-induced DNA synthesis in H-35 rat hepatoma cells. Based on the sequence data and functional analysis, we conclude that the mouse Ahsg gene is the true ortholog of the human AHSG gene.

Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes.

OBJECTIVE: To determine the efficacy of rosiglitazone compared with placebo in reducing hyperglycemia. RESEARCH DESIGN AND METHODS: After a 4-week placebo run-in period, 959 patients were randomized to placebo or rosiglitazone (total daily dose 4 or 8 mg) for 26 weeks. The primary measure of efficacy was change in the HbA1c concentration. RESULTS: Rosiglitazone produced dosage-dependent reductions in HbA1c of 0.8, 0.9, 1.1, and 1.5% in the 4 mg o.d., 2 mg b.i.d., 8 mg o.d., and 4 mg b.i.d. groups, respectively, compared with placebo. Clinically significant decreases from baseline in HbA1c were observed in drug-naive patients at all rosiglitazone doses and in patients previously treated with oral monotherapy at rosiglitazone 8 mg o.d. and 4 mg b.i.d. Clinically significant decreases from baseline in HbA1c were also observed with rosiglitazone 4 mg b.i.d. in patients previously treated with combination oral therapy. Approximately 33% of drug-naive patients treated with rosiglitazone achieved HbA1c < or =7% at study end. The proportions of patients with at least one adverse event were comparable among the rosiglitazone and placebo groups. There was no evidence of hepatotoxicity in any treatment group. There were statistically significant increases in weight and serum lipids in all rosiglitazone treatment groups compared with placebo. For LDL and HDL cholesterol, the observed increase appeared to be dose related. CONCLUSIONS: Rosiglitazone at total daily doses of 4 and 8 mg significantly improved glycemic control in patients with type 2 diabetes and was well tolerated.

C-peptide attenuates protein tyrosine phosphatase activity and enhances glycogen synthesis in L6 myoblasts.

Recent studies suggest that C-peptide might play a role in a broad range of biological activities. We have provided evidence that C-peptide stimulates glycogen synthesis in insulin-responsive rat skeletal muscle cells in a dose-related manner. To explore the mechanism by which C-peptide exerts this insulinomimetic effect, here we report the effect of C-peptide on protein tyrosine phosphatase (PTP) activity and phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1). C-peptide inhibited PTP activity in a dose-dependent manner. A reverse bell-shaped dose-response curve was shown with the maximum inhibition of PTP activity at a concentration of 3 nM of C-peptide, which is the same concentration achieving the maximum stimulatory effect on glycogen synthesis. In association with the PTP inhibition by C-peptide, autophosphorylation of the insulin receptor and activation of IRS-1 were enhanced. These results suggest that C-peptide signal transduction may crosstalk with the insulin signaling pathway at the level of the insulin receptor.

Proinsulin C-peptide--a consensus statement.

In recent years the physiological role of the proinsulin C-peptide has received increasing attention, focusing on the potential therapeutic value of C-peptide replacement in preventing and ameliorating type 1 diabetic complications. In order to consolidate these new data and to identify the immediate directions of C-peptide research and its clinical usefulness, an International Symposium was held in Detroit, Michigan, on October 20-21, 2000, under the auspices of the Wayne State University/Morris Hood Jr. Comprehensive Diabetes Center. In this communication, we review the cellular, physiological and clinical effects of C-peptide replacement in animal models and in patients with type 1 diabetes. Finally, recommendations are presented as to the most urgent studies that should be pursued to further establish the biological action of C-peptide and its therapeutic value.

Alpha2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor.

Human fetuin, [alpha2-Heremans Schmid Glycoprotein (alpha2-HSG)], is a natural inhibitor of insulin receptor tyrosine kinase activity (IR-TKA). Previously, we have demonstrated that alpha2-HSG inhibits the mitogenic pathway without affecting the metabolic arm of insulin signal transduction. In this study, we demonstrate the time-course and specificity of inhibition, its interaction with IR and probable physiological role. In intact rat1 fibroblasts overexpressing the human insulin receptor (HIRc B), incubation of recombinant human alpha2-HSGbac (1.8 microM) inhibited insulin-induced IR autophosphorylation by over 80%. This inhibitory effect of alpha2-HSGbac on insulin-induced IR autophosphorylation was blunted by half in 60 min. Interestingly, alpha2-HSGbac at similar concentrations (0.9 or 1.8 microM), had no effect on EGF- or IGF-I-induced cognate receptor autophosphorylation. Anti-alpha2-HSG immunoprecipitates of alpha2-HSGbac-treated HIRc B cell lysates demonstrated the presence of IR. Our data suggest that alpha2-HSGbac preferentially interacts with the activated IR. To further characterize the site(s) of interaction, the effect of alpha2-HSGbac on trypsin-treated IR autophosphorylation was studied. Trypsin-treatment of intact HIRc B cells results in proteolysis of the IR alpha-chain and constitutive activation of IR-TKA. We demonstrate that alpha2-HSGbac (0.1 microM) completely inhibited trypsin-activated IR autophosphorylation and TKA in vitro indicating that this effect was not mediated by its interaction with the proximal 576 amino acid residues of the IR alpha-subunit. The physiological relevance of these observations was explored by characterizing the effects of alpha2-HSG injection in rats. Alpha2-HSGbac (2 microM), acutely injected through the portal vein of normal rats, inhibited insulin-stimulated IR autophosphorylation and IRS-1 phosphorylation in liver and hindlimb muscle. Taken together our results suggest that alpha2-HSG, by interacting with IR, specifically inhibits insulin-stimulated IR autophosphorylation and may play a physiological role in the regulation of insulin signaling.

The influence of treatment modality and ethnicity on attitudes in type 2 diabetes.

OBJECTIVE: The study examines diabetes attitude differences by treatment modality (insulin vs. no insulin), race/ethnicity, and the interaction of these two variables for people with type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were collected with the Diabetes Care Profile (DCP), an instrument that assesses psychosocial factors related to diabetes. Participants (n = 672) were recruited in the metropolitan Detroit, Michigan, area from 1993 to 1996. A total of 68% of these participants were African-Americans with type 2 diabetes, and 32% were Caucasians with type 2 diabetes. Analyses of covariance were performed to examine the effects of race/ethnicity, treatment, and their interaction for each DCP scale. RESULTS: The four patient categories (two ethnicities by two treatment modalities) differed by age, years with diabetes, education, and sex distribution. Treatment modality had a significant effect on 6 of the 16 DCP scales (Control, Social and Personal Factors, Positive Attitude, Negative Attitude, Self-Care Ability, and Exercise Barriers). Ethnicity was a significant effect for three scales (Control, Support, and Support Attitudes). The interaction of race/ethnicity and treatment modality was a significant effect for two related attitude scales (Positive Attitude and Negative Attitude). CONCLUSIONS: The results suggest that attitudes toward diabetes are similar for African-American and Caucasian patients with type 2 diabetes. The results also suggest that treatment modality has a greater effect on attitudes than either race/ethnicity or the interaction effect. However, Caucasian patients using insulin differed from the other patient groups by having the least positive and the most negative attitudes regarding diabetes.

Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus.

BACKGROUND: C ardiac sympathetic signals play an important role in the regulation of myocardial perfusion. We hypothesized that sympathetically mediated myocardial blood flow would be impaired in diabetics with autonomic neuropathy. METHODS AND RESULTS: We studied 28 diabetics (43+/-7 years old) and 11 age-matched healthy volunteers. PET was used to delineate cardiac sympathetic innervation with [(11)C]hydroxyephedrine ([(11)C]HED) and to measure myocardial blood flow at rest, during hyperemia, and in response to sympathetic stimulation by cold pressor testing. The response to cardiac autonomic reflex tests was also evaluated. Using ultrasonography, we also measured brachial artery reactivity during reactive hyperemia (endothelium-dependent dilation) and after sublingual nitroglycerin (endothelium-independent dilation). Based on [(11)C]HED PET, 13 of 28 diabetics had sympathetic-nerve dysfunction (SND). Basal flow was regionally homogeneous and similar in the diabetic and normal subjects. During hyperemia, the increase in flow was greater in the normal subjects (284+/-88%) than in the diabetics with SND (187+/-80%, P=0.084) and without SND (177+/-72%, P=0.028). However, the increase in flow in response to cold was lower in the diabetics with SND (14+/-10%) than in those without SND (31+/-12%) (P=0.015) and the normal subjects (48+/-24%) (P<0.001). The flow response to cold was related to the myocardial uptake of [(11)C]HED (P<0.001). Flow-mediated brachial artery dilation was impaired in the diabetics compared with the normal subjects, but it was similar in the diabetics with and without SND. CONCLUSIONS: Diabetic autonomic neuropathy is associated with an impaired vasodilator response of coronary resistance vessels to increased sympathetic stimulation, which is related to the degree of SND.

Alpha2-Heremans Schmid glycoprotein inhibits insulin-stimulated Elk-1 phosphorylation, but not glucose transport, in rat adipose cells.

Alpha2-Heremans Schmid glycoprotein (alpha2-HSG) is a member of the fetuin family of serum proteins whose biological functions are not completely understood. There is a consensus that alpha2-HSG plays a role in the regulation of tissue mineralization. However, one aspect of alpha2-HSG function that remains controversial is its ability to inhibit the insulin receptor tyrosine kinase and the biological actions of insulin. Interestingly, some studies suggest that alpha2-HSG differentially inhibits mitogenic, but not metabolic, actions of insulin. However, these previous studies were not carried out in bona fide insulin target cells. Therefore, in the present study we investigate the effects of alpha2-HSG in the physiologically relevant rat adipose cell. We studied insulin-stimulated translocation of the insulin-responsive glucose transporter GLUT4 in transfected rat adipose cells overexpressing human alpha2-HSG. In addition, we measured insulin-stimulated glucose transport in adipose cells cultured with conditioned medium from the transfected cells as well as in freshly isolated adipose cells treated with purified human alpha2-HSG. Compared with control cells, we were unable to demonstrate any significant effect of alpha2-HSG on insulin-stimulated translocation of GLUT4 or glucose transport. In contrast, we did demonstrate that overexpression of alpha2-HSG in adipose cells inhibits both basal and insulin-stimulated phosphorylation of Elk-1 (a transcription factor phosphorylated and activated by mitogen-activated protein kinase and other related upstream kinases). Interestingly, we did not observe any major effects of alpha2-HSG to inhibit insulin-stimulated phosphorylation of the insulin receptor, insulin receptor substrate-1, -2, or -3, in either transfected or freshly isolated adipose cells. We conclude that alpha2-HSG inhibits insulin-stimulated Elk-1 phosphorylation, but not glucose transport, in adipose cells by a mechanism that may involve effector molecules downstream of insulin receptor substrate proteins.

The reliability of the Diabetes Care Profile for African Americans.

The Diabetes Care Profile (DCP) is an instrument used to assess social and psychological factors related to diabetes and its treatment. The reliability of the DCP was established in populations consisting primarily of Caucasians with type 2 diabetes. This study tests whether the DCP is a reliable instrument for African Americans with type 2 diabetes. Both African American (n = 511) and Caucasian (n = 235) patients with type 2 diabetes were recruited at six sites located in the metropolitan Detroit area. Scale reliability was calculated by Cronbach's coefficient alpha. The scale reliabilities ranged from .70 to .97 for African Americans. These reliabilities were similar to those of Caucasians, whose scale reliabilities ranged from .68 to .96. The Feldt test was used to determine differences between the reliabilities of the two patient populations. No significant differences were found. The DCP is a reliable survey instrument for African American and Caucasian patients with type 2 diabetes.

The safety of injecting insulin through clothing.

OBJECTIVE: Many of the "antiseptic" practices recommended by health care professionals for insulin injection have been successfully challenged as unnecessary. Since people with diabetes have long been observed to inject their insulin through their clothing, this study was undertaken to determine the safety and perceived benefits of administering insulin by this "rogue" technique. RESEARCH DESIGN AND METHODS: Fifty people with insulin-treated diabetes were randomized into a 20-week single-blinded prospective crossover study comparing the conventional subcutaneous injection technique (with skin preparation) to an experimental injection technique through clothing. Skin assessment, glycated hemoglobin levels, and leukocyte count were determined before randomization, at 10 weeks (before crossover), and again at 20 weeks (at completion). The participants injected through a single layer of fabric, which ranged from nylon to denim. Problems, benefits, type of clothing, and other comments were recorded by the subjects in an injection log. RESULTS: Forty-two (84%) subjects completed the study. The mean age was 41 years (range, 23-63 years), 50% were women, 86% were Caucasian, and 80% had type I diabetes. The mean duration of diabetes was 14 years (range, 1-33 years). Fifty-one percent had > 16 years of education. The demographic characteristics of the dropouts were similar to those who completed the study. Over the 20-week period approximately 13,720 injections were performed by participants. None of the subjects experienced erythema, induration, or abscess at injection sites. Neither the glycated hemoglobin levels nor the leukocyte counts differed between the conventional and experimental regimens. During the injection-through-clothing phase of the study, only minor problems, such as blood stains on clothing and bruising, were recorded in the logbooks. However, subjects reported that injection through clothing offered benefits such as convenience and saving time. CONCLUSIONS: It is safe and convenient to inject insulin through clothing.

Bovine fetuin is an inhibitor of insulin receptor tyrosine kinase.

Fetuin has been identified earlier as the bovine homolog of the human plasma protein, alpha2-Heremans Schmid glycoprotein (alpha2-HSG). Although bovine fetuin shares over 70% amino acid sequence similarity with alpha2-HSG and rat fetuin, no common function(s) have been identified. We report that immunoaffinity purified bovine fetuin acts as an inhibitor of insulin receptor tyrosine kinase activity (IR-TKA) with half-maximal inhibition at 1.5 microM. In vitro, bovine fetuin (1.5 microM) blocked insulin-induced autophosphorylation of the human IR completely and the half-maximal inhibitory effect was observed at 0.5 microM. Incubation of HIRcB cells (rat1 fibroblasts transfected with wild-type human insulin receptor cDNA) with bovine fetuin (1.5 microM) inhibited insulin-induced tyrosine phosphorylation of the IR beta-subunit by 40%. In addition, bovine fetuin (2 microM) completely blocked insulin-stimulated DNA synthesis in H-35 rat hepatoma cells. Our results, together with earlier reports on rat fetuin and human alpha2-HSG, indicate a common IR-TK inhibitory function for fetuin homologs.

Differences in the impact of dietary restrictions on African Americans and Caucasians with NIDDM.

African-American and Caucasian patients with non-insulin-dependent diabetes mellitus were surveyed to determine differences in self-reported dietary adherence. The relationship between dietary adherence and other psychosocial factors also was explored. The Diabetes Care Profile, an instrument designed to assess psychosocial factors related to diabetes, was completed by 178 patients. Correlation and regression analyses were used to examine the relationship between dietary adherence and 15 other scales in this instrument. Regression analyses revealed that selected scales were better at predicting dietary adherence for African Americans than for Caucasians. Self-care adherence was the most significant predictor of dietary adherence for African Americans while support was the most significant predictor for Caucasians. These findings suggest that cultural and social functions of food and diet should be examined and incorporated in the development of appropriate meal plans and educational interventions.