Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes.

AIM: G-protein coupled receptor agonists are currently under investigation for their potential utility in patients with type 2 diabetes mellitus (T2DM). The objective was to determine the pharmacokinetics, pharmacodynamics, safety and tolerability of GPR119 agonist, JNJ-38431055 in T2DM subjects. METHODS: This was a randomized, double-blind, placebo- and positive-controled, single-dose cross-over study and a randomized, double-blind, placebo-controled multiple-dose parallel design study. The study was conducted at 4 US research centres. Two different experiments involving 25 and 32 different subjects were performed in male and female subjects, aged 25-60 years, mean body mass index between 22 and 39.9 kg/m2 who had T2DM diagnosed 6 months to 10 years before screening. JNJ-38431055 (100 and 500 mg) or sitagliptin (100 mg) as a single-dose or JNJ-38431055 (500 mg) once daily for 14 consecutive days were tested. Effects on stimulated plasma glucose, insulin, C-peptide and incretin concentrations were pre-specified outcomes. RESULTS: JNJ-38431055 was well tolerated and not associated with hypoglycaemia. Plasma systemic exposure of JNJ-38431055 increased as the dose increased, was approximately two-fold greater after multiple-dose administration, and attained steady-state after approximately 8 days. Compared with placebo, single-dose administration of oral JNJ-38431055 decreased glucose excursion during an oral glucose tolerance test, but multiple-dose administration did not alter 24-h weighted mean glucose. Multiple dosing of JNJ-38431055 increased post-meal total glucagon-like peptide 1 and gastric insulinotropic peptide concentrations compared to baseline. CONCLUSIONS: These studies provide evidence of limited glucose lowering and incretin activity for JNJ-38431055 in subjects with T2DM.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects.

The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.

Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study.

OBJECTIVES: To evaluate the 2-year safety and efficacy of adding sitagliptin or glipizide to ongoing metformin in patients with type 2 diabetes. METHODS: Patients who were on a stable dose of metformin (> or = 1500 mg/day) for at least 8 weeks were randomised in a double-blind manner to receive either sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (up-titrated up to 20 mg/day based upon prespecified glycaemic criteria) (N = 584). The efficacy analysis assessed the change in HbA(1c) from baseline using the per-protocol (PP) population. RESULTS: For the PP cohort, mean baseline HbA(1c) was 7.3% in both groups. After 2 years, the least squares (LS) mean change in HbA(1c) from baseline [95% confidence interval (CI)] was -0.54% (-0.64, -0.45) with sitagliptin (n = 248) and -0.51% (-0.60, -0.42) with glipizide (n = 256). The rise in HbA(1c) from week 24 to week 104 [i.e. coefficient of durability (COD)] was smaller with sitagliptin [COD (95% CI) 0.16%/year (0.10, 0.21)] compared with glipizide [0.26%/year (0.21, 0.31)]. The proportion of patients with an HbA(1c)< 7% was 63% and 59% with sitagliptin and glipizide, respectively. The beta-cell responsiveness to a meal challenge was maintained with sitagliptin and decreased with glipizide. The proportion of patients who reported hypoglycaemia was 5% with sitagliptin and 34% with glipizide [difference in proportions (95% CI) = -29% (-33, -25)]. Relative to baseline, sitagliptin was associated with weight loss (-1.6 kg) compared with weight gain (+0.7 kg) with glipizide. CONCLUSION: In patients with type 2 diabetes, adding sitagliptin to metformin monotherapy improved glycaemic control over 2 years, similar to the glucose-lowering efficacy observed with adding glipizide, but with greater durability and generally better maintenance of beta-cell function. Sitagliptin was generally well tolerated with a lower risk of hypoglycaemia and weight loss compared with weight gain observed with glipizide.

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency.

OBJECTIVE: To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) > or =30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end-stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed. METHODS: In a 54-week, randomized, double-blind, parallel-group study, patients with baseline glycosylated haemoglobin A(1c) (HbA(1c)) values of 6.5-10% were allocated (2:1) to sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day. RESULTS: Patients (N = 91) with a mean baseline HbA(1c) value of 7.7% (range: 6.2-10.3%) were randomized to sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA(1c) was -0.6% (-0.8, -0.4) in the sitagliptin group compared with -0.2% (-0.4, 0.1) in the placebo group [between-group difference (95% CI) = -0.4% (-0.7, -0.1)]. At 54 weeks, patients continuously treated with sitagliptin had a mean change (95% CI) from baseline in HbA(1c) of -0.7% (-0.9, -0.4). The overall incidence of adverse experiences was generally similar between groups. Between-group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54-week study [5 of 65 patients (7.7%) in the sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug-related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups. CONCLUSIONS: In this study, sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.

Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on beta-cell function in patients with type 2 diabetes: a model-based approach.

PURPOSE: The purpose of this exploratory analysis was to assess the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on pancreatic beta-cell function using a model-based analysis. METHODS: Data for this analysis were from three large, placebo-controlled clinical studies that examined sitagliptin 100 mg q.d. as add-on to metformin therapy or as monotherapy over 18 or 24 weeks. In these studies, subsets of patients consented to undergo extensive blood sampling as part of a nine-point meal tolerance test performed at baseline and study end-point. Blood samples were collected at -10, 0, 10, 20, 30, 60, 90, 120 and 180 min relative to the start of a meal and subsequently were assayed for plasma glucose and serum C-peptide concentrations. Parameters for beta-cell function were calculated using the C-peptide minimal model, which estimates insulin secretion rate (ISR) and partitions the ISR into basal (Phi(b); ISR at basal glucose concentrations), static (Phi(s); ISR at above basal glucose concentrations following a meal) and dynamic (Phi(d); ISR in response to the rate of increase in above basal glucose concentrations following a meal) components. The total responsivity index (Phi(total); average ISR over the average glucose concentration) is calculated as a function of Phi(s), Phi(d )and Phi(b. )Insulin sensitivity was assessed with a validated composite index (ISI). Disposition indices (DI), which assess insulin secretion in the context of changes in insulin sensitivity, were calculated as the product of Phiand ISI. RESULTS: When administered in combination with ongoing metformin therapy or as monotherapy, sitagliptin was associated with substantial reductions in postprandial glycaemic excursion following a meal challenge relative to placebo. Sitagliptin produced significant (p < 0.05 vs. placebo) improvements in Phi(s )and Phi(total), regardless of treatment regimen (add-on to metformin or as monotherapy). For Phi(d), there was a numerical, but not statistically significant, improvement with sitagliptin relative to placebo. Treatment with sitagliptin increased Phi(b), but the difference relative to placebo was only significant with monotherapy. ISI was not significantly different between sitagliptin and placebo. The DIs for the static, dynamic and total measures were significantly (p < 0.05) increased with sitagliptin treatment relative to placebo. CONCLUSIONS: In this model-based analysis, sitagliptin improved beta-cell function relative to placebo in both fasting and postprandial states in patients with type 2 diabetes.

Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with Type 2 diabetes in UK primary care.

AIMS: To describe initial achievement of glycaemic targets and subsequent hyperglycaemia in patients with Type 2 diabetes managed with oral agent monotherapy in UK primary care from 1998 to 2004. METHODS: Electronic medical records of patients initiating metformin (n = 3362) or a sulphonylurea agent (n = 3070) in 290 UK primary care practices were retrieved from the General Practice Research Database (GPRD). Patients included had an HbA(1c) recorded 0-90 days before and 90-365 days after initiating monotherapy. The probability of achieving glycaemic thresholds in the first year, and for those achieving such targets, the probability of inadequate glycaemic control (HbA(1c) > 6.5%, > 7.0%, > 7.5%) over time is described. RESULTS: Low baseline HbA(1c) and drug initiation within 3 months of diabetes diagnosis were the strongest predictors of initial achievement of glycaemic targets. The proportion of patients with diabetes duration > or = 4 months who achieved HbA(1c) < 7% in the first year ranged from 24% to 88% for highest to lowest baseline HbA(1c) category in sulphonylurea initiators and from 19% to 86% in metformin initiators, with slightly higher proportions for newly diagnosed patients. Kaplan-Meier analyses suggested that 55% and 70% of patients who initially achieved glycaemic targets had HbA(1c) measurements above these targets at 2 and 3 years. CONCLUSIONS: Many patients fail to achieve glycaemic goals with initial monotherapy and, of those who achieve current goals, few consistently maintain these targets over 3 years. Research is needed to evaluate whether more aggressive treatment or alternative treatments can improve the long-term maintenance of glycaemic control in patients with Type 2 diabetes.

Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin.

Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a new class of oral antihyperglycemic agents to treat patients with type 2 diabetes. DPP-4 inhibitors improve fasting and postprandial glycemic control without hypoglycemia or weight gain. This article focuses on the physiology, clinical pharmacology, tolerability, and clinical utility of the DPP-4 inhibitor sitagliptin in the management of type 2 diabetes.

Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes.

AIM: The aim of this study was to assess the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on 24-h glucose control when added to the regimen of patients with type 2 diabetes who had inadequate glycaemic control on metformin therapy. METHODS: In a double-blind, randomized, placebo-controlled, two-period crossover study, patients with type 2 diabetes with inadequate glycaemic control on metformin monotherapy (i.e. on a stable dose of > or = 1500 mg/day for > or = 6 weeks prior to the screening visit and an haemoglobin A(1c) (HbA(1c)) > or = 6.5% and <10% and fasting plasma glucose (FPG) < or = 240 mg/dl) were recruited for participation. A total of 28 patients (baseline HbA(1c) range = 6.5-9.6%) receiving metformin were randomized into one of two treatment sequences: the addition of placebo for 4 weeks followed by the addition of sitagliptin 50 mg twice daily (b.i.d.) for 4 weeks, or vice versa. At the end of each treatment period, patients were domiciled for frequent blood sampling over 24 h. The primary endpoint was 24-h weighted mean glucose (WMG) and secondary endpoints included change in FPG, mean of 7 daily self-blood glucose measurements (MDG) and fructosamine. beta-cell function was assessed from glucose and C-peptide concentrations were measured during the 5-h period after a standard breakfast meal by using the C-peptide minimal model. RESULTS: Despite a carryover effect from period 1 to period 2, the combined period 1 and period 2 results for glycaemic endpoints were statistically significant for sitagliptin relative to placebo when added to ongoing metformin therapy. To account for the carryover effect, the period 1 results were also compared between the groups. Following period 1, there were significant least-squares (LS) mean reductions in 24-h WMG of 32.8 mg/dl, significant LS mean reduction from baseline in MDG of 28 mg/dl, FPG of 20.3 mg/dl and fructosamine of 33.7 mmol/l in patients treated with sitagliptin relative to placebo (p < 0.05). When added to ongoing metformin therapy, parameters of beta-cell function were significantly improved with sitagliptin compared with placebo. No weight gain or increases in gastrointestinal adverse events or hypoglycaemia events were observed with sitagliptin relative to placebo during this study. CONCLUSIONS: In this study, the addition of sitagliptin 50 mg b.i.d. to ongoing metformin therapy improved 24-h glycaemic control and beta-cell function, and was generally well tolerated in patients with type 2 diabetes.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial.

AIM: To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate glycaemic control [haemoglobin A(1c) (HbA(1c)) > or = 6.5 and < or = 10%] on metformin monotherapy. METHODS: After a metformin dose titration/stabilization period (> or = 1500 mg/day), 1172 patients were randomized to the addition of sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N = 584) for 52 weeks. The primary analysis assessed whether sitagliptin was non-inferior to glipizide regarding HbA(1c) changes from baseline at Week 52 using a per-protocol approach. RESULTS: From a mean baseline of 7.5%, HbA(1c) changes from baseline were -0.67% at Week 52 in both groups, confirming non-inferiority. The proportions achieving an HbA(1c) < 7% were 63% (sitagliptin) and 59% (glipizide). Fasting plasma glucose changes from baseline were -0.56 mmol/l (-10.0 mg/dl) and -0.42 mmol/l (-7.5 mg/dl) for sitagliptin and glipizide, respectively. The proportion of patients experiencing hypoglycaemia episodes was significantly (p < 0.001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide-treated patients compared with 50 events in sitagliptin-treated patients. Sitagliptin led to weight loss (change from baseline =-1.5 kg) compared with weight gain (+1.1 kg) with glipizide [between-treatment difference (95% confidence interval) =-2.5 kg (-3.1, -2.0); p < 0.001]. CONCLUSIONS: In this study, the addition of sitagliptin compared with glipizide provided similar HbA(1c)-lowering efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide.

The many 'faces' of Graves' disease. Part 2. Practical diagnostic testing and management options.

Recognition of the many "faces" of Graves' disease can lead to earlier detection and management. Diagnosis is not always obvious, and this common multisystem syndrome requires attentive clinical evaluation. New laboratory and nuclear medicine diagnostic procedures now allow precise biochemical and pathophysiologic confirmation of the disease. Beta blockers promptly alleviate symptoms, allowing time for thoughtful consideration by patient and physician as to optimal definitive therapy with antithyroid drugs, RAI, or surgery.

The many 'faces' of Graves' disease. Part 1. Eyes, pulse, skin, and neck provide important clues to diagnosis.

The variety in clinical appearance of patients with Graves' disease suggests that predominant symptoms affecting one body system may be either compelling or misleading to clinicians during the initial assessment. However, each patient in these case presentations had additional bedside evidence of many of the recognized multisystem manifestations of hyperthyroidism, as detected on more extensive evaluation. Laboratory tests confirmed the diagnosis in each instance. While these cases are not meant to represent all reported manifestations of Graves' disease, grouping of symptoms into memorable "faces" is helpful for definitive clinical recognition and precise diagnosis of this complex and challenging syndrome.

The role of diet in the genesis and treatment of hypertension.

In this brief review, we have not been able to address all of the various dietary factors which have been implicated as causal in hypertension. Because of the heterogeneity of hypertension, it is quite difficult to find a simple answer to the question of how important dietary factors are in causing hypertension and even more difficult to answer the question of how diet should be therapeutically altered in treating a hypertensive patient. Given the difficulties in achieving good compliance to almost any dietary prescription and the lifestyle changes these therapies often require, significant benefit must be demonstrated to justify the efforts. It is worth emphasizing that many of the dietary alterations which have been proposed for treating hypertension have even better established preventative health rationales which justify their use. Although salt intake is a factor in the genesis of hypertension, the effectiveness of salt restriction varies between patients. Despite the absence of good predictors of response, moderate sodium reduction is a reasonable first step when dealing with a hypertensive patient. In obese hypertensive patients, weight loss provides a modest but significant BP reduction. Added benefit may be obtained by lowering total fat content and increasing the ratio of polyunsaturated to saturated fats. The reduction in cardiovascular risk with these changes in dietary fat, over and above the lowering of BP, make this approach appropriate in all hypertensive patients. Potassium supplementation, while sometimes effective, is more difficult to recommend broadly. Calcium supplementation is certainly reasonable in women, for whom such therapy should be seen as good dietary advice for the prevention of osteoporosis. Moderate alcohol intake probably has little deleterious effect, whereas heavy alcoholism does contribute to increased BP. Again, reduction of alcohol intake is important for reasons other than the modest BP reduction attained.

The effect of CP 68,722, a thiozolidinedione derivative, on insulin sensitivity in lean and obese Zucker rats.

The effect of a new drug (CP 68,722, Pfizer) on parameters of insulin sensitivity in an established insulin-resistant animal model was examined. Rates of hepatic glucose production (HGP) and peripheral glucose uptake in obese Zucker (fa/fa) rats treated with a 10-day course of the medication using a two-step (2 and 10 mU/kg/min) euglycemic hyperinsulinemic clamp technique were measured. In addition, changes in substrate concentrations after drug treatment were examined. Basal HGP rates were similar in the lean versus the obese animals (37 +/- 3 v 39 +/- 3 mumol/kg/min); however, the obese animals had impaired insulin-induced suppression of HGP at both 2 mU/kg/min (36 +/- 3 v 23 +/- 4 mumol/kg/min) and 10 mU/kg/min (18 +/- 5 v 2 +/- 1 mumol/kg/min). Insulin stimulation of glucose disposal was also defective in the obese animals (37 +/- 2 v 88 +/- 7 mumol/kg/min at 2 mU/kg/min and 98 +/- 9 v 219 +/- 18 mumol/kg/min at 10 mU/kg/min). In addition, obese animals had elevated free fatty acid (FFA) and ketone levels, both of which were resistant to insulin-induced suppression. After drug treatment, few alterations in glucose or lipid metabolism were found in the lean animals. In the obese animals, insulin suppression of HGP was normalized during the higher insulin infusion rate (0 v 18 +/- 5 mumol/kg/min at 10 mU/kg/min), and peripheral glucose disposal was enhanced at both steps of the insulin clamp (54 +/- 4 v 37 +/- 2 mumol/kg/min at 2 mU/kg/min and 134 +/- 12 v 98 +/- 9 mumol/kg/min at 10 mU/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Drug treatment of hypertension in patients with diabetes mellitus.

Patients with diabetes mellitus have an increased prevalence of hypertension and its vascular consequences, including coronary and cerebrovascular disease. Drug treatment of hypertension in diabetic subjects is fraught with potential difficulties, including the altered efficacy of medications, the increased risk of side effects, and the possibility of worsening glycemic control and increasing serum lipid levels. Despite these difficulties, treatment is an important part of reducing morbidity and mortality from vascular events. Antihypertensive therapy may also have the potential to prevent or retard the development of diabetic nephropathy. In this article, we discuss the efficacy and metabolic and nonmetabolic side effects of the various classes of antihypertensive agents in patients with diabetes mellitus and suggest a stepped-care approach to the drug treatment of patients with hypertension and diabetes.

A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience.

Pheochromocytoma is an unusual but potentially devastating tumor. Although a high index of suspicion is necessary, the likelihood of a pheochromocytoma is lower in the absence of the typical symptoms and findings. Nonetheless, screening must be broadened to include patients with a lower risk of the disease, such as those with resistant or labile hypertension who are minimally symptomatic. Extensive diagnostic evaluations should be reserved for those whose clinical or laboratory findings are more suggestive. Symptoms in a group of patients in whom a pheochromocytoma was seriously considered but excluded overlap symptoms in patients with a pheochromocytoma. Certain symptoms are useful: flushing to suggest a non-pheochromocytoma illness; visual symptoms, flank pain, and pallor to suggest that a pheochromocytoma is more likely. Combinations of symptoms can be of value: 2 or more symptoms from the triad of headache, palpitations, and diaphoresis were present in the majority of pheochromocytoma patients, but in a smaller number of non-pheochromocytoma patients. The presence of the entire triad is more specific, but less sensitive. New hypertension, or hypertension associated with unexplained orthostatic hypotension, are suggestive of an underlying pheochromocytoma. Twenty-four-hour urine studies are consistently abnormal in patients with a pheochromocytoma, but are also elevated in a significant proportion of non-pheochromocytoma patients. Values greater then 1.5-2-fold above the upper limit of normal are very suggestive that a pheochromocytoma is present, and warrant a more intensive subsequent evaluation. Imaging studies are reliable in the diagnosis of pheochromocytoma, and can help to confirm or exclude the disease. Patients with a higher clinical likelihood and any elevated urinary testing, or with a lower clinical likelihood and persistently and/or significantly elevated urinary testing, should have imaging studies performed. This combination of clinical screening, 24-hour urinary testing, and imaging studies is a useful and reliable approach to patients suspected of harboring a pheochromocytoma.

Insulin resistance in uremia: an in vivo and in vitro study.

Insulin-mediated glucose metabolism was examined in vivo and in vitro in a chronically uremic (4-week) rat model established by a 90% nephrectomy. Using the euglycemic insulin clamp technique, uremic rats demonstrated a 28% reduction (P less than .01) in total body glucose disposal compared with pair-fed controls. Suppression of hepatic glucose production by insulin was not impaired. The ability of insulin to promote glycogen synthesis by the soleus muscle in vitro was normal in uremic rats. In contrast, the ability of insulin to enhance both glycolysis and glucose oxidation by the soleus muscle was significantly reduced (P less than .01) in uremic rats. These results provide evidence that at least two intracellular metabolic defects, ie, in the glycolytic and glucose oxidative pathways, contribute to the insulin resistance of chronic uremia.