R. Ravi Shankar

Glucosamine infusion in rats mimics the β-cell dysfunction of non—insulin-dependent diabetes mellitus

Sustained hyperglycemia can cause peripheral insulin resistance and pancreatic beta-cell dysfunction and has been termed glucose toxicity or glucose-induced desensitization. Glucosamine, a product of glucose flux through the hexosamine biosynthetic pathway (HBP), causes insulin resistance in peripheral tissues and has been shown to cause abnormal glucose-insulin secretion coupling, and thus has been implicated in the pathogenesis of glucose toxicity. Here, we investigate whether glucosamine-induced insulin secretory dysfunction is specific to glucose or also extends to nonglucose secretagogues such as arginine. Two groups of 12 weight-matched Sprague-Dawley rats underwent hyperglycemic clamp studies (steady-state blood glucose, approximately 220 mg x dL(-1)) during infusion of normal saline or glucosamine 3.5 mg x kg(-1) x min(-1) over a 100-minute period. Insulin levels were measured at baseline and between 90 and 100 minutes. One hundred minutes into the hyperglycemic clamp, subgroups of seven rats each (saline- and glucosamine-infused rats) received a bolus of arginine (100 mg x kg(-1)) while the glucose infusion rate was unaltered. Glucose and insulin levels were measured at 1, 3, 5, 10, 15, and 30 minutes after the arginine bolus. Both groups had similar fasting glucose and insulin levels. At steady state (60 to 100 minutes), glucose levels were almost identical in both groups (223.58+/-3.94 v 224.58+/-4.34 mg x dL(-1)), but the glucose infusion rate (26.55+/-1.60 v 8.83+/-1.35 mg x kg(-1) x min(-1), P < .0001) and insulin level (41.36+/-6.47 v 18.04+/-2.95 mU x mL(-1), P < .0001) were markedly reduced in animals receiving glucosamine. Peak insulin levels 1 minute after the arginine bolus were lower in rats infused with glucosamine versus saline (274.00+/-30.38 v 176.25+/-20.12 microU x ml(-1), P=.0319). Total insulin secretion in response to arginine was significantly lower in the glucosamine group as determined by the area under the curve (1,268.09+/-142.27 v 706.77+/-84.79 microU x mL(-1) x min, P=.0054). In conclusion, glucosamine causes severe impairment in glucose-induced insulin secretion. Further, glucosamine-induced beta-cell secretory dysfunction extends to nonglycemic stimuli like arginine. This pattern of insulin secretory dysfunction is similar to that observed in patients with non-insulin-dependent diabetes mellitus (NIDDM). These data suggest that glucosamine may participate in the pathogenesis of glucose toxicity at the level of the beta cell in NIDDM patients.

IV insulin during acute cerebral infarction in diabetic patients

Although hyperglycemia can be a nonspecific response to stress, tight glycemic control during acute myocardial infarction1 and in postoperative ventilated patients2 has been shown to significantly reduce mortality. Animal3 and human4-6⇓⇓ studies suggest that hyperglycemia also augments acute cerebral ischemia, and clinical efficacy of tight glycemic control during acute cerebral infarction is being investigated.7 Good glycemic control during acute cerebral infarction in nondiabetic patients appears feasible and safe, but this has not been reported in patients with diabetes mellitus.7 Our Institutional Review Board approved this study, and all subjects signed a valid informed consent. We prospectively administered an IV insulin protocol initiated within 12 hours after onset of cerebral infarction to 24 consecutive patients with admission hyperglycemia (9.4 to 22.2 mmol/L or 170 to 400 mg/dL). Nurses supervised closely by the principal investigator administered the insulin protocol in an open-label fashion. We modified our insulin protocol after each three to seven treated subjects to improve glycemic control and minimize hypoglycemia while keeping the protocol practical. We adjusted the insulin …

Treating Postprandial Hyperglycemia Does Not Appear to Delay Progression of Early Type 2 Diabetes The Early Diabetes Intervention Program

OBJECTIVE—Postprandial hyperglycemia characterizes early type 2 diabetes. We investigated whether ameliorating postprandial hyperglycemia with acarbose would prevent or delay progression of diabetes, defined as progression to frank fasting hyperglycemia, in subjects with early diabetes (fasting plasma glucose [FPG] <140 mg/dl and 2-h plasma glucose ≥200 mg/dl). RESEARCH DESIGN AND METHODS—Two hundred nineteen subjects with early diabetes were randomly assigned to 100 mg acarbose t.i.d. or identical placebo and followed for 5 years or until they reached the primary outcome (two consecutive quarterly FPG measurements of ≥140 mg/dl). Secondary outcomes included measures of glycemia (meal tolerance tests, HbA1c, annual oral glucose tolerance tests [OGTTs]), measures of insulin resistance (homeostasis model assessment [HOMA] of insulin resistance and insulin sensitivity index from hyperglycemic clamps), and secondary measures of β-cell function (HOMA-β, early- and late-phase insulin secretion, and proinsulin-to-insulin ratio). RESULTS—Acarbose significantly reduced postprandial hyperglycemia. However, there was no difference in the cumulative rate of frank fasting hyperglycemia (29% with acarbose and 34% with placebo; P = 0.65 for survival analysis). There were no significant differences between groups in OGTT values, measures of insulin resistance, or secondary measures of β-cell function. In a post hoc analysis of subjects with initial FPG <126 mg/dl, acarbose reduced the rate of development of FPG ≥126 mg/dl (27 vs. 50%; P = 0.04). CONCLUSIONS—Ameliorating postprandial hyperglycemia did not appear to delay progression of early type 2 diabetes. Factors other than postprandial hyperglycemia may be greater determinants of progression of diabetes. Alternatively, once FPG exceeds 126 mg/dl, β-cell failure may no longer be remediable.

TAMOXIFEN TREATMENT OF PROGRESSIVE PRECOCIOUS PUBERTY IN A PATIENT WITH MCCUNE-ALBRIGHT SYNDROME

Treatment of progressive precocious puberty in patients with McCune-Albright syndrome (MAS) has traditionally been with aromatase inhibitors, such as testolactone. However, the use of these agents has been characterized by problems with both efficacy and compliance. We report a case of MAS in which tamoxifen proved to be a successful alternative in the treatment of progressive precocious puberty. An African-American female presented with MAS at 2-5/12 years. Frequent menses, skeletal maturation and growth acceleration prompted initiation of therapy with testolactone at 22 mg/kg/d. Over the next 13 months, the patients puberty advanced unchecked, despite progressive increases in the dose of testolactone. At age 4 years, medication was discontinued due to treatment failure. At 4-6/12 years, bone age was 10 years, predicted adult height was 137 cm, and monthly bleeding continued. Tamoxifen was then begun on an experimental basis. In response, the patient experienced immediate cessation of menses, and had an abrupt decrease in the rates of pubertal progression and linear growth. This patient has now been maintained on tamoxifen for over three years with no apparent adverse effects. GnRH analogue therapy was begun when the onset of central precocious puberty was noted. Predicted adult height has improved to 154 cm and growth velocity and skeletal maturation remain stable. Our results suggest that tamoxifen may have a valuable role in the treatment of precocious puberty in patients with MAS and may lead to superior results compared with those achieved with aromatase inhibitors.

The Use of Tamoxifen to Improve Height Potential in Short Pubertal Boys

A retrospective chart review of 7 pubertal boys who were treated with tamoxifen was conducted to determine the effects of this therapy on skeletal maturation and predicted adult height. Tamoxifen significantly decreased the rate of skeletal maturation and increased the predicted adult height without negative effects on sexual maturation. Additional evaluation of this therapy is now required to determine if the increase in predicted adult height results in a clinically significant increase in final adult height.

Tamoxifen Treatment of Progressive Precocious Puberty in a Patient With McCune-Albright Syndrome |[dagger]| 420

Treatment of progressive precocious puberty in patients with McCune-Albright syndrome (MAS) has traditionally been with aromatase inhibitors, such as testolactone. However, the use of these agents has been characterized by problems with both efficacy and compliance. We report a case of MAS in which tamoxifen proved to be a successful alternative in the treatment of progressive precocious puberty. An African-American female presented with MAS at 2-5/12 years. Frequent menses, skeletal maturation and growth acceleration prompted initiation of therapy with testolactone at 22 mg/kg/d. Over the next 13 months, the patients puberty advanced unchecked, despite progressive increases in the dose of testolactone. At age 4 years, medication was discontinued due to treatment failure. At 4-6/12 years, bone age was 10 years, predicted adult height was 137 cm, and monthly bleeding continued. Tamoxifen was then begun on an experimental basis. In response, the patient experienced immediate cessation of menses, and had an abrupt decrease in the rates of pubertal progression and linear growth. This patient has now been maintained on tamoxifen for over three years with no apparent adverse effects. GnRH analogue therapy was begun when the onset of central precocious puberty was noted. Predicted adult height has improved to 154 cm and growth velocity and skeletal maturation remain stable. Our results suggest that tamoxifen may have a valuable role in the treatment of precocious puberty in patients with MAS and may lead to superior results compared with those achieved with aromatase inhibitors.

Factors Associated with Severe Hypoglycemia among Patients with Type 2 Diabetes Treated with Insulin

We have previously reported that rates of severe hypoglycemic events (SHEs, defined as events that required hospitalization or an emergency department visit) are higher in patients with type 2 diabetes (T2D) on insulin alone (3.4%) or insulin+SU (2.5%) compared to those on insulin+other anti-hyperglycemic agents (AHA) (1.6%). The present analyses were conducted to further evaluate the independent risk factors of SHE after accounting for differences in two treatment groups based on propensity for SHE: Insulin±SU and Insulin+Other AHA. This retrospective analysis using MarketScan database included T2D adults (n=202,147; mean age: 54.0 years; 53% females) with a first prescription of insulin from 1/1/2013 to 12/31/2013 (index period). SHE was measured from the index date to the end of follow-up (12/31/2013). Multivariable Poisson regression was performed to compare the risk of SHE between insulin±SU vs. insulin+other AHA users and assess other predictors. The unadjusted SHE rate per 100 person years was 2.2% among all patients; 2.8% among those on insulin±SU and 1.3% among those on insulin+other AHA. After adjusting for patient’s baseline characteristics, the risk of SHE was 84% higher in patients on insulin±SU compared to those on insulin+other AHA [Hazard ratio (HR):1.84; 95% confidence interval (CI): 1.68- 2.01]. In addition to the treatment type, other factors predictive of SHE were previous history of SHE (HR: 4.73; 95% CI: 4.33- 5.17); and history of comorbidities including chronic kidney disease (HR: 1.75; 95% CI: 1.60-1.92), cardiovascular disease (HR: 1.60; 95% CI: 1.46-1.75), and neuropathy (HR: 1.55; 95% CI: 1.43-1.69). Our results suggest the risk of SHE is lower in patients on insulin with other AHA compared to patients on insulin alone or with SU. Healthcare professionals should take into account the risk of having SHE while making treatment choices especially for vulnerable populations such as patients with prior history of SHE, and other comorbidities. Disclosure M. Pawaskar: Employee; Self; Merck & Co., Inc. J. Liu: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; Anthem, Inc.. Employee; Self; Janssen Scientific Affairs, LLC. R. Shankar: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; NGM Biopharmaceuticals. S. Rajpathak: Employee; Self; Merck & Co., Inc..

Hyperpigmentation in Only One Identical Twin

A 10 year-old previously healthy female presented to the hospital in the winter season with vomiting and lethargy. Laboratory studies showed hypoglycemia (42 mg/dl), hyponatremia (126 mmol/l), hyperkalemia (5.7 mmol/l), and acidosis (bicarbonate 12 mmol/l). She was also hypotensive with a Doppler blood pressure of 68/22. She subsequently recovered with intravenous fluid hydration and glucose. She tested positive for influenza A, and she was discharged home with a suspected viral illness. She returned to the hospital exactly one month later with similar symptoms, and on examination it was noted that her skin was now tan when compared to her identical twin sister (Picture). She also had a hyperpigmented scar on her right knee and hyperpigmentation of her umbilicus (Picture). Her baseline cortisol level was 1.3 µg/dl and rose to 1.8 µg/dl after a high dose ACTH (250 µg) stimulation test. Additional testing revealed primary autoimmune adrenal insufficiency (Addison’s disease). Her symptoms improved after starting hydrocortisone and fludrocortisone. Nearly four years later, her identical twin remains disease free.

About Hyperglycemia During Acute Stroke

To the Editor: Having completed a pilot clinical trial of aggressive hyperglycemia correction during acute cerebral infarction, we read with interest the recently published American Heart Association guidelines that include new suggestions for managing hyperglycemia during acute stroke.1 Although the guidelines clearly declare their lack of support by clinical trials (grade or level C), they suggest a relatively aggressive and ambiguous approach. The discussion section suggests that initiating treatment when glucose is >200 mg/dL …