Treatment with basal/bolus regimen with detemir once daily and aspart before meals results in equivalent glycemic control and no differences in the frequency of hypoglycemia compared to a split-mixed regimen of NPH and regular insulin in patients with type 2 diabetes.

The molecular mechanisms of heparan sulfate proteoglycan downregulation in the glomerular basement membrane (GBM) of the kidneys with diabetic nephropathy remain controversial. In the present study, we showed that the expression of heparanase-1 (HPR1), a heparan sulfate-degrading endoglycosidase, was upregulated in the renal epithelial cells in the kidney with diabetic nephropathy. Urinary HPR1 levels were elevated in patients with diabetic nephropathy. In vitro cell culture studies revealed that HPR1 promoterdriven luciferase reporter gene expression, HPR1 mRNA, and protein were upregulated in renal epithelial cells under high glucose conditions. Induction of HPR1 expression by high glucose led to decreased cell surface heparan sulfate expression. HPR1 inhibitors were able to restore cell surface heparan sulfate expression. Functional analysis revealed that renal epithelial cells grown under high glucose conditions resulted in an increase of basement membrane permeability to albumin. Our studies suggest that loss of heparan sulfate in the GBM with diabetic nephropathy is attributable to accelerated heparan sulfate degradation by increased HPR1 expression. Diabetes 54:2172-2178, 2005 D iabetic nephropathy is a major cause of endstage renal disease. It is characterized by glomerular hemodynamic abnormalities that result in glomerular hyperfiltration, leading to glomerular damage as evidenced by microalbuminuria. As glomerular function continues to decline, overt proteinuria, decreased glomerular filtration rate, and end-stage renal failure result. The glomerular basement membrane (GBM) functions as a primary barrier to allow molecules to selectively cross over into the urinary space (1). The GBM is a specialized extracellular matrix produced as a thin sheet-like structure by glomerular epithelial cells (1). The main components in the GBM are collagen type IV, laminin, and heparan sulfate proteoglycans (HSPGs) (1). HSPGs are composed of a protein core attached with side-chains of the complex glycosaminoglycan heparan sulfate (2). Because of their negative charge, heparan sulfate chains are highly hydrated and thus play a key space-filling and molecular-sieving role in the GBM. It has been long recognized that ultrastructural changes, including GBM thickening, mesangial expansion, and reduction in HSPGs, lead to the loss of charge selectivity and altered glomerular size selectivity, allowing albumin leakage into the urinary space.Heparanase-1 (HPR1) is an endoglycosidase that specifically degrades HSPGs. Several lines of evidence suggest that HPR1 plays a critical role in the pathogenesis of proteinuria in diabetic nephropathy: 1) heparin and other glycosaminoglycans, which have been recently identified as heparanase inhibitors (3), can slow down diabetic nephropathy in preclinical and clinical settings (4); 2) recent studies demonstrated that glomerular charge selectivity is greatly compromised in mice treated with bacterial heparinase and other glycosaminoglycan-degrading enzymes (5); and 3) overexpression of HPR...

OBJECTIVE -We studied a systematic program to reeducate our medical house officers on how to manage inpatient hyperglycemia without the use of sliding-scale insulin (SSI).RESEARCH DESIGN AND METHODS -Patients admitted to the general medical service with diabetes or a blood glucose Ͼ140 mg/dl were included. HbA 1c was measured in all patients, and therapy was modified if the HbA 1c was Ͼ7.0%. For each 24 h on call, two house officers were responsible for all glucose management for their team's patients and rounded with a teaching endocrinologist twice daily for 2 weeks. Oral agent or insulin therapy was modified using blood glucoses and HbA 1c . All patients who required insulin therapy were treated with basal and bolus insulin, usually NPH and regular, adjusted twice daily.RESULTS -During 8 weeks, 88 patients were identified and 16 house officers were instructed. The mean duration of diabetes was 10.4 years. Mean HbA 1c level was 8.7%, and 48% of patients had HbA 1c Ͼ8%. All patients with HbA 1c Ͼ7% had diabetes therapy intensified. Overall 80% had their diabetes therapy changed by discharge. Compared with 98 historical control subjects, significantly fewer study patients had episodes of hyperglycemia, and a subgroup followed for 12 months showed a decrease in HbA 1c from 10.1 to 8%. CONCLUSIONS -Medical history, blood glucose, and HbA 1c testing can effectively identify patients with inpatient hyperglycemia. Using direct ward-based teaching and a widely disseminated pocket set of guidelines, house officers can be taught to effectively and safely manage inpatient hyperglycemia without the use of SSI. Diabetes Care 28:1008 -1011, 2005D iabetes is one of the most common diagnoses encountered in hospitalized patients (1). In 1997, diabetes was the fourth most common comorbid condition in hospital discharges, and 9.5% of all hospital discharges listed diabetes as a diagnosis upon discharge (2). The majority of hospitalizations for patients with diabetes are due to comorbid conditions, and diabetes management is not a focus during inpatient stays (3,4). However, inpatient hyperglycemia has been associated with nosocomial infections, increased mortality, and increased length of stay (5).As in most American hospitals, the use of sliding-scale insulin (SSI) for the treatment of inpatient hyperglycemia was common practice at Rush University Medical Center before our study. Typically an order is written for diabetic patients upon admission that provides a predetermined amount of subcutaneous regular insulin, usually beginning with 2 units for blood glucose Ͼ150 or 200 mg/ dl. The order calls for the insulin dose to be increased by 2 units for every 50-mg/dl increase in blood glucose. Previous outpatient diabetes therapy is commonly discontinued on admission, especially if patients are NPO (nothing per os).While it has long been recognized that SSI has many drawbacks, its use in the inpatient setting has been a reflex action passed down from attending physicians to residents to medical students for the past several generat...

Insulin isolated from the pancreas of a diabetic patient with fasting hyperinsulinaemia showed decreased activity in binding to cell membrane insulin receptors and in stimulating cellular 2-deoxyglucose transport and glucose oxidation. Chemical studies suggest that the isolated hormone is a mixture of normal insulin and an abnormal variant which contains a leucine for phenylalanine substitution at position 24 or 25 of the insulin B-chain.

BackgroundHypoglycemia is common in patients with end-stage renal disease (ESRD). We identified the incidence and timing of hypoglycemia and its risk factors in hospitalized patients with ESRD after the treatment of hyperkalemia with insulin.MethodsWe conducted a retrospective study of all hospitalized adult patients treated with hemodialysis who received intravenous insulin to treat hyperkalemia between 1 January 2011 and 31 December 2011. We identified patients who became hypoglycemic [blood glucose <3.3 mmol/L (60 mg/dL)] after insulin administration.ResultsTwo hundred and twenty-one episodes of hyperkalemia were treated with insulin, resulting in 29 episodes of hypoglycemia (13%). Factors associated with a higher risk of hypoglycemia included no prior diagnosis of diabetes [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.0–5.1, P = 0.05], no use of diabetes medication prior to admission [OR 3.6, 95% CI 1.2–10.7, P = 0.02] and a lower pretreatment glucose level [mean 5.8 ± 0.7 mmol/L (104 ± 12 mg/dL) versus 9.0 ± 0.6 mmol/L (162 ± 11 mg/dL), P = 0.04]. Hypoglycemia occurred at a median of 2 h after insulin administration and persisted for a median of 2 h.ConclusionsThe treatment of hyperkalemia with insulin in hospitalized patients with ESRD may be complicated by hypoglycemia. Patients with a history of diabetes are less susceptible to this complication. Our study supports the use of a protocol to provide dextrose support and blood glucose monitoring for at least 3 h after insulin treatment of hyperkalemia.

A B S T R A C T Five patients with fasting and(or) postprandial hypoglycemia were found to have insulin antibodies in the absence of previously documented immunization. Studies on the equilibrium-binding of insulin to the autoantibodies revealed two classes of binding sites with association constants and binding capacities analogous to those of insulin antibodies from insulin-treated diabetic patients. Similarly, no consistent differences in these parameters were found in both groups of patients with insulins ofbovine, porcine, and human origin. Proinsulin (C-segment directed) antibodies capable ofbinding bovine or porcine proinsulin were present in 10 of 10 and 9 of 10 insulin-treated diabetics serving as controls, respectively, and, when present, provide incontrovertible evidence of exogenous insulin administration. No such antibodies could be detected in the hypoglycemic patients with autoimmune insulin antibodies.The kinetics of dissociation of the insulin-antibody complexes were consistent with the existence of two classes of antibody sites. The corresponding dissociation rate constants were large enough to predict that significant amounts of free hormone may be generated by this mechanism and provide a plausible pathogenesis for the hypoglycemia in these patients.

Aims: The use of incretin-based therapy, rather than or complementary to, insulin therapy is an active area of research in hospitalized patients with type 2 diabetes (T2D). We determined the glycaemic efficacy and safety of linagliptin compared to a basal-bolus insulin regimen in hospitalized surgical patients with T2D. Materials and Methods:This prospective open-label multicentre study randomized T2D patients undergoing non-cardiac surgery with admission blood glucose (BG) of 7.8 to 22.2 mmol/L who were under treatment with diet, oral agents or total insulin dose (TDD) ≤ 0.5 units/kg/day to either linagliptin (n = 128) daily or basal-bolus (n = 122) with glargine once daily and rapid-acting insulin before meals. Both groups received supplemental insulin for BG > 7.8 mmol/L. The primary endpoint was difference in mean daily BG between groups.Results: Mean daily BG was higher in the linagliptin group compared to the basal-bolus group (9.5 AE 2.6 vs 8.8 AE 2.3 mmol/L/dL, P = 0.03) with a mean daily BG difference of 0.6 mmol/L (95% confidence interval 0.04, 1.2). In patients with randomization BG < 11.1 mmol/L (63% of cohort), mean daily BG was similar in the linagliptin and basal-bolus groups (8.9 AE 2.3 vs 8.7 AE 2.3 mmol/L, P = 0.43); however, patients with BG ≥ 11.1 mmol/L who were treated with linagliptin had higher BG compared to the basal-bolus group (10.9 AE 2.6 vs 9.2 AE 2.2 mmol/L, P < 0.001). Linagliptin resulted in fewer hypoglycaemic events (1.6% vs 11%, P = 0.001; 86% relative risk reduction), with similar supplemental insulin and fewer daily insulin injections (2.0 AE 3.3 vs 3.1 AE 3.3, P < 0.001) compared to the basal-bolus group.Conclusions: For patients with T2D undergoing non-cardiac surgery who presented with mild to moderate hyperglycaemia (BG < 11.1 mmol/L), daily linagliptin is a safe and effective alternative to multi-dose insulin therapy, resulting in similar glucose control with lower hypoglycaemia.The association between hyperglycaemia and poor clinical outcomes in patients with and without diabetes is well established. 1-5 Extensive data from observational and prospective randomized controlled trials in hospitalized patients have resulted in a strong association between hyperglycaemia and poor clinical outcomes, such as increased mortality, morbidity, length of hospital stay (LOS), infections and overall complications. 1,4,6-8 Most clinical trials in critically ill and in noncritically ill medicine and surgery patients with hyperglycaemia and diabetes have reported that improved glycaemic control reduces LOS, risk of multi-organ failure and systemic infections, 9-12 as well as short-and long-term mortality, 6,11 although the largest trial in critically ill patients showed increased mortality with intensive glucose control. 12 Current clinical guidelines from professional societies recommend basal-bolus insulin regimens as the standard of care for hospitalized patients with type 2 diabetes (T2D). 13,14 Our group has shown that a basal-bolus insulin regimen resulted in improved glycaemic co...

OBJECTIVERenal insufficiency may increase the risk of hypoglycemia in hospitalized patients with diabetes who are treated with insulin. We randomized inpatients with type 2 diabetes and chronic renal failure to treatment with two different dose levels of insulin glargine and glulisine and studied control of hyperglycemia and the frequency of hypoglycemia.RESEARCH DESIGN AND METHODSWe conducted a multicenter, prospective, randomized trial to compare the efficacy of once-daily glargine and three-times daily glulisine at 0.5 vs. 0.25 units/kg/day. A total of 107 subjects had type 2 diabetes for >1 year, had a glomerular filtration rate <45 mL/min but did not require dialysis, and had an initial blood glucose (BG) >180 mg/dL. Doses were adjusted based on four-times daily BG measurements for 6 days.RESULTSMean BG on the first day was 196 ± 71 mg/dL in the group receiving 0.5 units/kg (0.5 group) and 197 ± 55 mg/dL in the group receiving 0.25 units/kg (0.25 group; P = 0.94). On days 2 to 6, mean BG was 174 ± 52 mg/dL in the 0.5 group and 174 ± 46 mg/dL in the 0.25 group (P = 0.96). There were no significant differences between groups in the percentage of BG values within the target range of 100 to 180 mg/dL on any of the 6 study days. In the 0.5 group, 30% experienced hypoglycemia (BG <70 mg/dL) compared with 15.8% of the 0.25 group (P = 0.08).CONCLUSIONSReduction of initial glargine/glulisine insulin weight-based dosing in hospitalized patients with diabetes and renal insufficiency reduced the frequency of hypoglycemia by 50% without compromising the control of hyperglycemia.