Dawn Smiley

Randomized Study of Basal-Bolus Insulin Therapy in the Inpatient Management of Patients With Type 2 Diabetes Undergoing General Surgery (RABBIT 2 Surgery)

OBJECTIVE The optimal treatment of hyperglycemia in general surgical patients with type 2 diabetes mellitus is not known. RESEARCH DESIGN AND METHODS This randomized multicenter trial compared the safety and efficacy of a basal-bolus insulin regimen with glargine once daily and glulisine before meals (n = 104) to sliding scale regular insulin (SSI) four times daily (n = 107) in patients with type 2 diabetes mellitus undergoing general surgery. Outcomes included differences in daily blood glucose (BG) and a composite of postoperative complications including wound infection, pneumonia, bacteremia, and respiratory and acute renal failure. RESULTS The mean daily glucose concentration after the 1st day of basal-bolus insulin and SSI was 145 ± 32 mg/dL and 172 ± 47 mg/dL, respectively (P < 0.01). Glucose readings <140 mg/dL were recorded in 55% of patients in basal-bolus and 31% in the SSI group (P < 0.001). There were reductions with basal-bolus as compared with SSI in the composite outcome [24.3 and 8.6%; odds ratio 3.39 (95% CI 1.50–7.65); P = 0.003]. Glucose <70 mg/dL was reported in 23.1% of patients in the basal-bolus group and 4.7% in the SSI group (P < 0.001), but there were no significant differences in the frequency of BG <40 mg/dL between groups (P = 0.057). CONCLUSIONS Basal-bolus treatment with glargine once daily plus glulisine before meals improved glycemic control and reduced hospital complications compared with SSI in general surgery patients. Our study indicates that a basal-bolus insulin regimen is preferred over SSI in the hospital management of general surgery patients with type 2 diabetes.

Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery.

OBJECTIVE Hospital hyperglycemia, in individuals with and without diabetes, has been identified as a marker of poor clinical outcome in cardiac surgery patients. However, the impact of perioperative hyperglycemia on clinical outcome in general and noncardiac surgery patients is not known. RESEARCH DESIGN AND METHODS This was an observational study with the aim of determining the relationship between pre- and postsurgery blood glucose levels and hospital length of stay (LOS), complications, and mortality in 3,184 noncardiac surgery patients consecutively admitted to Emory University Hospital (Atlanta, GA) between 1 January 2007 and 30 June 2007. RESULTS The overall 30-day mortality was 2.3%, with nonsurvivors having significantly higher blood glucose levels before and after surgery (both P < 0.01) than survivors. Perioperative hyperglycemia was associated with increased hospital and intensive care unit LOS (P < 0.001) as well as higher numbers of postoperative cases of pneumonia (P < 0.001), systemic blood infection (P < 0.001), urinary tract infection (P < 0.001), acute renal failure (P = 0.005), and acute myocardial infarction (P = 0.005). In multivariate analysis (adjusted for age, sex, race, and surgery severity), the risk of death increased in proportion to perioperative glucose levels; however, this association was significant only for patients without a history of diabetes (P = 0.008) compared with patients with known diabetes (P = 0.748). CONCLUSIONS Perioperative hyperglycemia is associated with increased LOS, hospital complications, and mortality after noncardiac general surgery. Randomized controlled trials are needed to determine whether perioperative diabetes management improves clinical outcome in noncardiac surgery patients.

Narrative Review: Ketosis-Prone Type 2 Diabetes Mellitus

In 1987, Winter and colleagues (1) reported a small cohort of young African-American patients who, despite presenting with severe hyperglycemia or diabetic ketoacidosis, subsequently had clinical and metabolic features of type 2 diabetes. Obesity was present in 46% of these patients, and their insulin secretion in response to mixed-meal stimulation was intermediate between that seen in nondiabetic controls and in patients with type 1 diabetes. They called this form of diabetes atypical diabetes. During the past decade, this clinical presentation of diabetes has been increasingly recognized and is believed to account for 25% to 50% of African-American and Hispanic persons with new diagnoses of diabetic ketoacidosis (2-8). Although most cases are reported in African persons and in African-American individuals in the United States, atypical diabetes has also been reported in Native-American (9), Japanese (10, 11), Chinese (12-14), Hispanic (15, 16), and white (15, 17) populations. Because of the mixed features of type 1 and type 2 diabetes, this variant of type 2 diabetes has been referred to in the literature as diabetes type 1B, idiopathic type 1 diabetes, atypical diabetes, Flatbush diabetes, type 1.5 diabetes, and more recently, ketosis-prone type 2 diabetes (1, 3, 4, 6, 15, 18-20). The aims of this review are to review current information regarding the clinical presentation, metabolic and immunologic features, and pathogenesis of ketosis-prone type 2 diabetes and to share our experience in the management of adult patients with this atypical form of the disease. We did a computerized search of biomedical journal literature from MEDLINE, PubMed, and Ovid from 1966 to October 2005. We reviewed English-language original and review articles found under the subject headings ketosis-prone type 2 diabetes and atypical diabetes. Historical Background During the past 5 decades, case studies from Nigeria, Congo, Tanzania, and other sub-Saharan countries have reported small series of patients with atypical presentation of diabetes (6, 18, 19, 21-24). In the 1960s, Adadevoh (23) and Dodu (21) reported that some adult patients with diabetic ketoacidosis were able to discontinue insulin therapy after a relative short time and remain in near-normoglycemic remission for several months to years. This unique, transient insulin-requiring profile was recognized mainly in patients with newly diagnosed diabetes and was reported as temporary diabetes in adult Nigerians. Subsequent reports from other African groups noted the difficulty in classifying such patients as having type 1 and type 2 diabetes during their initial presentation (22, 24). In the United States, an atypical form of diabetes was first reported in 12 African-American youths (1). Ten of these patients were admitted to the hospital with diabetic ketoacidosis, and 2 were admitted with severe hyperglycemia. The diabetes in these patients was characterized by an acute presentation, an autosomal dominant pattern of inheritance, negative islet-cell antibodies, and an insulin response to mixed meals that was intermediate between that seen in nondiabetic controls and in patients with type 1 diabetes. In contrast to the long-term insulin requirement of type 1 diabetes, these patients discontinued insulin therapy and maintained acceptable glycemic control for many years either by diet or by taking oral agents. In 1994, Banerji and colleagues (4) reported 21 patients with diabetic ketoacidosis who had similar characteristics except for older age at onset and a lower prevalence of obesity. All of these patients were black, were mostly of Caribbean origin, and were labeled as having Flatbush diabetes in recognition of the region in New York where most of them resided. The researchers also recognized the presence of measurable pancreatic insulin reserve, absence of autoimmune indicators of -cell destruction, and increased frequency of HLA-DR3 and HLA-DR4. Subsequently, our group reported on the clinical, metabolic, and immunogenetic features of 2 large cohorts of black patients presenting with unprovoked diabetic ketoacidosis (2, 3, 25). We showed that patients with ketosis-prone type 2 diabetes have a severe but transient defect in insulin secretion and insulin action, which partially resolves after a few weeks of insulin therapy and is followed by near-normoglycemic remission that may last for several months to years. Prevalence The prevalence of ketosis-prone type 2 diabetes is not known, but observational studies suggest that this type of diabetes accounts for a substantial number of patients with diabetic ketoacidosis. In the United States, the prevalence has been estimated to be between 20% and 50% in African-American and Hispanic patients with new diagnoses of diabetic ketoacidosis (3, 16, 25-27). In addition to ethnicity, clinical features predictive of future near-normoglycemic remission are obesity and a family history of type 2 diabetes. Among 154 consecutive African-American patients admitted to the hospital with diabetic ketoacidosis, we observed that obesity was present in 29% and that the prevalence of obesity was higher among those with newly diagnosed diabetes (56%) (25). More than 80% of patients have a family history of type 2 diabetes. The mean body mass index at presentation in African-American patients with ketosis-prone type 2 diabetes has ranged between 28 kg/m2 to 37 kg/m2 (2, 5, 6, 25). A high rate of obesity is also reported in Hispanic (16, 20) and Chinese (13) persons and in sub-Saharan black African immigrants to Europe (6 18, 19). Obesity in persons with diabetic ketoacidosis from minority ethnic groups is more common than in white persons, in whom the rate of obesity is less than 20% (28, 29). Balasubramanyan and colleagues (27) reviewed the clinical profiles of 141 adults admitted to the hospital with diabetic ketoacidosis. At presentation, 39% of patients were considered to have type 1 diabetes, 53% were considered to have type 2 diabetes, and 8% were not classified. Twenty-eight percent of patients had newly diagnosed diabetes, 93% of whom were reassessed at least 2 years after their initial episode of diabetic ketoacidosis and were considered to have type 2 diabetes (27). More recently, Piero-Piloa and Raskin (20) reported that the incidence of this type of diabetes among persons with new-onset diabetes with diabetic ketoacidosis was approximately 60%. In agreement with the U.S. experience, African studies have reported that 42% to 64% of patients with diabetic ketoacidosis initially treated with insulin therapy do not have classic type 1 diabetes and may experience prolonged remission (7, 22, 23, 30). The prevalence of ketosis-prone type 2 diabetes seems to be lower in Asian and white persons and may represent fewer than 10% of cases of diabetic ketoacidosis (13, 15, 31). Clinical Presentation Most adults with ketosis-prone type 2 diabetes are obese, middle-aged persons with newly diagnosed diabetes who present with unprovoked diabetic ketoacidosis (Table 1). The initial presentation is usually acute. These patients have a history of polyuria, polydipsia, and weight loss for less than 4 to 6 weeks (2, 6, 17, 25). The mean age at diagnosis is 40 years (SD, 2) (range, 33 to 53 years). More than three fourths of patients with ketosis-prone type 2 diabetes present as having new-onset diabetes. Several series of patients with ketosis-prone type 2 diabetes show a 2- or 3-fold higher prevalence in men (2, 6, 17, 20, 25). This is in contrast to series of white patients with type 1 diabetes, which report that women are more likely than men to develop diabetic ketoacidosis (29, 32). The male predominance in ketosis-prone type 2 diabetes seems to be independent of the degree of obesity and age at presentation. The reason for the sex difference is unknown; however, it has been attributed to hormonal factors, body fat distribution, and changes in insulin sensitivity (20). Table 1. Clinical Characteristics of Patients with Ketosis-Prone Type 2 Diabetes Physical examination reveals signs of dehydration, dry mucous membranes, and tachycardia. Substantial hypotension or changes in mental status are seldom seen at admission. Glucose level and acidbase parameters at presentation are similar to those reported in lean patients with diabetic ketoacidosis. In our series (2, 3, 25, 33), the mean level of glucose at admission has ranged between 38 to 40 mmol/L (684 to 720 mg/dL), with a mean serum bicarbonate level of 12 to 14 mmol/L, pH level of 7.22 to 7.25, and hemoglobin A1c level between 12% and 14% (2, 3, 25, 33). Clinical Course Few studies have analyzed the clinical course and predictors of near-normoglycemic remission in adults with diabetic ketoacidosis (Table 2). McFarlane and colleagues (5) described the clinical course of African-American persons from Brooklyn admitted to the hospital with newly diagnosed ketoacidosis who were followed for at least 1 year. Remission was defined as a hemoglobin A1c level of 6.3% or less and a fasting plasma glucose level of less than 6.6 mmol/L (<120 mg/dL) 3 months after therapy with all pharmacologic agents was discontinued. Forty-two percent of patients achieved remission after a mean of 83 days and remained in remission during 20 months of follow-up. There were no differences in age, sex, plasma glucose level at presentation, changes in body mass index, magnitude of weight change, or pharmacologic agents used between patients who achieved remission and those who did not. We also observed that near-normoglycemic remission was achieved in 70% of obese African-American patients after 9 weeks of follow-up (2, 6, 33). More recently, Mauvais-Jarvis and colleagues (6) reported that discontinuation of insulin therapy with subsequent remission was achieved in 76% of sub-Saharan African patients with diabetic ketoacidosis after a mean of 14.3 weeks (range, 1 to 150 weeks) of insulin therapy. Ten years after their first presenta

Comparison of Inpatient Insulin Regimens with Detemir plus Aspart Versus Neutral Protamine Hagedorn plus Regular in Medical Patients with Type 2 Diabetes

BACKGROUND Studies comparing the use of basal bolus with insulin analogs vs. split-mixed regimens with human insulins in hospitalized patients with type 2 diabetes are lacking. RESEARCH DESIGN AND METHODS In a controlled multicenter trial, we randomized 130 nonsurgical patients with blood glucose (BG) between 140 and 400 mg/dl to receive detemir once daily and aspart before meals (n = 67) or neutral protamine Hagedorn (NPH) and regular insulin twice daily (n = 63). Insulin dose was started at 0.4 U/kg.d for BG between 140 and 200 mg/dl or 0.5 U/kg.d for BG 201-400 mg/dl. Major study outcomes included differences in mean daily BG levels and frequency of hypoglycemic events between treatment groups. RESULTS Glycemic control improved similarly in both groups from a mean daily BG of 228 +/- 54 and 223 +/- 58 mg/dl (P = 0.61) to a mean daily BG level after the first day of 160 +/- 38 and 158 +/- 51 mg/dl in the detemir/aspart and NPH/regular insulin groups, respectively (P = 0.80). A BG target below 140 mg/dl before meals was achieved in 45% of patients in the detemir/aspart group and 48% in the NPH/regular group (P = 0.86). During treatment, 22 patients (32.8%) in the detemir/aspart group and 16 patients (25.4%) in the NPH/regular group had at least one episode of hypoglycemia (BG < 60 mg/dl) during the hospital stay (P = 0.34). CONCLUSIONS 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.

Randomized Study Comparing a Basal Bolus With a Basal Plus Correction Insulin Regimen for the Hospital Management of Medical and Surgical patients With Type 2 Diabetes: Basal Plus Trial

OBJECTIVE Effective and easily implemented insulin regimens are needed to facilitate hospital glycemic control in general medical and surgical patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This multicenter trial randomized 375 patients with T2D treated with diet, oral antidiabetic agents, or low-dose insulin (≤0.4 units/kg/day) to receive a basal-bolus regimen with glargine once daily and glulisine before meals, a basal plus regimen with glargine once daily and supplemental doses of glulisine, and sliding scale regular insulin (SSI). RESULTS Improvement in mean daily blood glucose (BG) after the first day of therapy was similar between basal-bolus and basal plus groups (P = 0.16), and both regimens resulted in a lower mean daily BG than did SSI (P = 0.04). In addition, treatment with basal-bolus and basal plus regimens resulted in less treatment failure (defined as >2 consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL) than did treatment with SSI (0 vs. 2 vs. 19%, respectively; P < 0.001). A BG <70 mg/dL occurred in 16% of patients in the basal-bolus group, 13% in the basal plus group, and 3% in the SSI group (P = 0.02). There was no difference among the groups in the frequency of severe hypoglycemia (<40 mg/dL; P = 0.76). CONCLUSIONS The use of a basal plus regimen with glargine once daily plus corrective doses with glulisine insulin before meals resulted in glycemic control similar to a standard basal-bolus regimen. The basal plus approach is an effective alternative to the use of a basal-bolus regimen in general medical and surgical patients with T2D.

Hyperglycemia during total parenteral nutrition: an important marker of poor outcome and mortality in hospitalized patients.

OBJECTIVE To determine the effect of total parenteral nutrition (TPN)-induced hyperglycemia on hospital outcome. RESEARCH DESIGN AND METHODS The study determined whether blood glucose values before, within 24 h, and during days 2–10 of TPN are predictive of hospital complications and mortality. RESULTS Subjects included a total of 276 patients receiving TPN for a mean duration of 15 ± 24 days (±SD). In multiple regression models adjusted for age, sex, and diabetes status, mortality was independently predicted by pre-TPN blood glucose of 121–150 mg/dl (odds ratio [OR] 2.2, 95% CI 1.1–4.4, P = 0.030), 151–180 mg/dl (3.41, 1.3–8.7, P = 0.01), and >180 mg/dl (2.2, 0.9–5.2, P = 0.077) and by blood glucose within 24 h of >180 mg/dl (2.8, 1.2–6.8, P = 0.020). A blood glucose within 24 h of >180 mg/dl was associated with increased risk of pneumonia (OR 3.1, 95% CI 1.4–7.1) and acute renal failure (2.3, 1.1–5.0). CONCLUSIONS Hyperglycemia is associated with increased hospital complications and mortality in patients receiving TPN.

Insulin Analogs Versus Human Insulin in the Treatment of Patients With Diabetic Ketoacidosis: A randomized controlled trial

OBJECTIVE To compare the safety and efficacy of insulin analogs and human insulins both during acute intravenous treatment and during the transition to subcutaneous insulin in patients with diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS In a controlled multicenter and open-label trial, we randomly assigned patients with DKA to receive intravenous treatment with regular or glulisine insulin until resolution of DKA. After resolution of ketoacidosis, patients treated with intravenous regular insulin were transitioned to subcutaneous NPH and regular insulin twice daily (n = 34). Patients treated with intravenous glulisine insulin were transitioned to subcutaneous glargine once daily and glulisine before meals (n = 34). RESULTS There were no differences in the mean duration of treatment or in the amount of insulin infusion until resolution of DKA between intravenous treatment with regular and glulisine insulin. After transition to subcutaneous insulin, there were no differences in mean daily blood glucose levels, but patients treated with NPH and regular insulin had a higher rate of hypoglycemia (blood glucose <70 mg/dl). Fourteen patients (41%) treated with NPH and regular insulin had 26 episodes of hypoglycemia and 5 patients (15%) in the glargine and glulisine group had 8 episodes of hypoglycemia (P = 0.03). CONCLUSIONS Regular and glulisine insulin are equally effective during the acute treatment of DKA. A transition to subcutaneous glargine and glulisine after resolution of DKA resulted in similar glycemic control but in a lower rate of hypoglycemia than with NPH and regular insulin. Thus, a basal bolus regimen with glargine and glulisine is safer and should be preferred over NPH and regular insulin after the resolution of DKA.

Recurrent Diabetic Ketoacidosis in Inner-City Minority Patients: Behavioral, socioeconomic, and psychosocial factors

OBJECTIVE To conduct a bedside study to determine the factors driving insulin noncompliance in inner-city patients with recurrent diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS We analyzed socioeconomic and psychological factors in 164 adult patients with DKA who were admitted to Grady Hospital between July 2007 and August 2010, including demographics, diabetes treatment, education, and mental illness. The Patient Health Questionnaire-9 and the Short Form-36 surveys were used to screen for depression and assess quality of life. RESULTS The average number of admissions was 4.5 ± 7 per patient. A total of 73 patients presented with first-time DKA, and 91 presented with recurrent DKA; 96% of patients were African American. Insulin discontinuation was the leading precipitating cause in 68% of patients; other causes were new-onset diabetes (10%), infection (15%), medical illness (4%), and undetermined causes (3%). Among those who stopped insulin, 32% gave no reasons for stopping, 27% reported lack of money to buy insulin, 19% felt sick, 15% were away from their supply, and 5% were stretching insulin. Compared with first-time DKA, those with recurrent episodes had longer duration of diabetes (P < 0.001), were a younger age at the onset of diabetes (P = 0.04), and had higher rates of depression (P = 0.04), alcohol (P = 0.047) and drug (P < 0.001) abuse, and homelessness (P = 0.005). There were no differences in quality-of-life scores, major psychiatric illnesses, or employment between groups. CONCLUSIONS Poor adherence to insulin therapy is the leading cause of recurrent DKA in inner-city patients. Several behavioral, socioeconomic, psychosocial, and educational factors contribute to poor compliance. The recognition of such factors and the institution of culturally appropriate interventions and education programs might reduce DKA recurrence in minority populations.

Safety and Efficacy of Sitagliptin Therapy for the Inpatient Management of General Medicine and Surgery Patients With Type 2 Diabetes: A pilot, randomized, controlled study

OBJECTIVE This study investigated the safety and efficacy of sitagliptin (Januvia) for the inpatient management of type 2 diabetes (T2D) in general medicine and surgery patients. RESEARCH DESIGN AND METHODS In this pilot, multicenter, open-label, randomized study, patients (n = 90) with a known history of T2D treated with diet, oral antidiabetic agents, or low total daily dose of insulin (≤0.4 units/kg/day) were randomized to receive sitagliptin alone or in combination with glargine insulin (glargine) or to a basal bolus insulin regimen (glargine and lispro) plus supplemental (correction) doses of lispro. Major study outcomes included differences in daily blood glucose (BG), frequency of treatment failures (defined as three or more consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL), and hypoglycemia between groups. RESULTS Glycemic control improved similarly in all treatment groups. There were no differences in the mean daily BG after the 1st day of treatment (P = 0.23), number of readings within a BG target of 70 and 140 mg/dL (P = 0.53), number of BG readings >200 mg/dL (P = 0.23), and number of treatment failures (P > 0.99). The total daily insulin dose and number of insulin injections were significantly less in the sitagliptin groups compared with the basal bolus group (both P < 0.001). There were no differences in length of hospital stay (P = 0.78) or in the number of hypoglycemic events between groups (P = 0.86). CONCLUSIONS Results of this pilot indicate that treatment with sitagliptin alone or in combination with basal insulin is safe and effective for the management of hyperglycemia in general medicine and surgery patients with T2D.

Intravenous Intralipid-Induced Blood Pressure Elevation and Endothelial Dysfunction in Obese African-Americans with Type 2 Diabetes

OBJECTIVE Increased free fatty acids (FFAs) are leading candidates in the pathogenesis of insulin resistance and hypertension in obese subjects. We evaluated the effect of sustained elevations of FFA on blood pressure, endothelial function, insulin secretion, inflammatory markers, and renin-angiotensin system. RESEARCH DESIGN AND METHODS Twenty-four obese, African-American, normotensive diabetic subjects received a sequential 48-h infusion of Intralipid (20%, 40 ml/h) plus heparin (250 units/h) or normal saline (40 ml/h) plus heparin (250 units/h). RESULTS Blood pressure was significantly increased within 4 h of lipid infusion and reached a peak increment of 13 mm Hg in systolic and 5 mm Hg in diastolic blood pressure at 24 h (P < 0.01). Compared to baseline, lipid infusion reduced flow-mediated dilatation by 11% at 24 h and 18% at 48 h (P < 0.001). FFA and triglyceride levels increased from a baseline of 0.5 +/- 0.2 mmol/liter and 135 +/- 76 mg/dl to 1.8 +/- 1.0 mmol/liter and 376 +/- 314 mg/dl at 48 h, respectively (P < 0.01). C-Reactive protein increased by 35% at 24 h and by 110% at 48 h of lipid infusion. There were no significant changes in plasma renin and aldosterone levels during lipid or saline infusions. CONCLUSION Increased FFA levels result in a rapid and sustained elevation in blood pressure, impaired endothelial function, and increased inflammatory markers in obese subjects with type 2 diabetes. The model of FFA-induced hypertension may be useful in examining disease mechanisms associated with the development of hypertension in obese subjects.