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SUMMARY To assess the relative contribution of overproduction and underutilization of glucose and ketone bodies to the development of diabetic ketoacidosis in man, the effects of acute insulin deficiency on glucose and ketone body turnovers were determined in seven ketosis-prone (type I) diabetic subjects. After termination of prolonged intravenous infusions of insulin, which had been maintaining the subjects euglycemic, plasma free insulin decreased from 18 ± 4 μU/ml to 7 ± 1 μU/ml, P < 0.01; plasma glucagon increased from 67 ± 6 pg/ml to 259 ± 67 pg/ml, P < 0.05, but plasma growth hormone and cortisol did not increase. Plasma glucose increased from 5.4 ± 0.3 mM to 15.6 ± 1.0 mM, P < 0.01; plasma ketone bodies (β-hydroxybutyrate plus acetoacetate) increased from 1.4 ± 0.4 mM to 7.2 ± 1.5 mM, P < 0.01. Glucose production increased abruptly from 13.2 ± 1.1 μmol/kgmin to a maximum of 26.1 ± 2.9 μmol/kg-min at 2 h but then decreased toward baseline rates; glucose utilization also increased transiently. In contrast, both ketone body production and utilization increased progressively throughout the study from 5.4 ± 1.4 and 5.5 ± 1.1 to 18.3 ± 3.9 and 14.7 ± 2.1 μmol/kg-min, respectively, P < 0.01. Clearance of both glucose and ketone bodies decreased more than 50%, P < 0.01. These results indicate that overproduction of glucose and ketone bodies is the primary process involved in the initiation of diabetic ketoacidosis in man. However, persistent overproduction of glucose and ketone bodies may not be necessary for the maintenance of hyperglycemia and hyperketonemia, since clearance of both substrates is impaired. Finally, since, of all counter-insulin hormones measured, only plasma glucagon increased coincident with increases in glucose and ketone body production, these results provide further evidence that glucagon may be the most important counter-insulin hormone involved in the genesis Of ketoacidosis.

The responses of glucagon, growth hormone, and insulin secretion to the oral administration of glucose and to the intravenous infusion of saline, arginine, and insulin were measured in seven patients who had stable diabetes, eight who had unstable diabetes, and seven healthy volunteers. Hyperglycemia suppressed secretion of glucagon in normal subjects but not in diabetics. The oral glucose and arginine infusion tests demonstrated partial preservation of insulin-secretory ability in stable diabetics and its virtual absence in unstable diabetics. Glucagon responses to arginine infusion were similar in all three groups. In response to hypoglycemia induced by insulin infusion, the concentrations of plasma glucagon increased in normal subjects and, to a lesser extent, in stable diabetics but increased in only two of the unstable diabetics. The impairment in glucagon response during hypoglycemia in diabetics correlated positively with the degree of diabetic instability and insulin deficiency during glucose and arginine testing. The severity of the insulin deficiency also correlated with the degree of diabetic instability. These findings support the hypothesis that inherent abnormalities of insulin and glucagon secretion may account for many of the clinical characteristics of unstable and stable diabetic patients.

The incidence and prevalence of diabetes mellitus in residents of Rochester, Minnesota, for 25 years (1945 to 1970) were determined from available medical records. The over-all incidence rate for diabetes is 133 new cases per 100,000 population per year (age-adjusted to 1970 U.S. white population). The rate increased with age for both men and women and was higher among men over 30 years of age. The average annual incidence rates per five-year period for juvenile-onset diabetes mellitus were low and variable and showed little change. Polyuria, polydipsia, glycosuria, lean habitus, loss of weight, and high levels of fasting hyperglycemia at initial diagnosis occurred more frequently in younger than in older patients. The peak incidence in 1960 through 1964 and the decrease in the following five years may be a reflection of the introduction of the AutoAnalyzer method for blood glucose in 1958. The average annual incidence rates for 1955 through 1959 and 1965 through 1969 were essentially the same. The over-all prevalence for diabetes mellitus is 1.6 per cent, with a higher rate among men than among women over 40 years of age; among school children the rate is 0.1 per cent. Survivorship in the diabetic population is lower than that in the general population. The leading cause of death was coronary heart disease, the death rate from it being higher than for the general population.

Excess free fatty acid release (rate of appearance) is seen in overnight postabsorptive, upper body obese women and, if present postprandially, could contribute to glucose intolerance. These studies examine the antilipolytic effect of a mixed meal in upper body obese, lower body obese, and nonobese women and the contribution of meal triglyceride fatty acids to circulating free fatty acids. Eight upper body obese, 8 lower body obese, and 8 nonobese age-matched, premenopausal women were studied. Systemic oleate Ra ([3H]oleate) was measured before and after an evening meal that contained triolein labeled with [14C]triolein as the only source of fat. Premeal oleate Ra was greater in both upper body obese and lower body obese women than nonobese women. The nadir of total oleate Ra occurred 90–240 min postprandially and was less (P < 0.01) in nonobese and lower body obese women (63 ± 10 and 87 ± 17 μmol/min) than in upper body obese women (140 ± 21 μmol/min). Meal oleate Ra contributed substantially to total oleate Ra. The nadir for endogenous oleate Ra in nonobese and lower body obese women was less (P < 0.01) than that observed in upper body obese women. We conclude that the antilipolytic effect of a mixed meal is reduced in upper body obese women and that meal triglyceride fatty acids contribute significantly to postprandial free fatty acid flux.

As part of a multicenter trial, 70 individuals with insulin-dependent diabetes were randomized to either conventional insulin therapy (CIT) or continuous subcutaneous insulin infusion (CSII). In order to standardize patient selection in the six participating centers, one of the eligibility criteria was the demonstration that each patient had no residual endogenous insulin secretion as assessed by plasma C-peptide determinations. The patients were of average (± SEM) age of 33.0 ± 1.6 yr, had had diabetes for a mean (±SEM) duration of 17.4 ± 1.1 yr, and had both fasting and postglucagon stimulation C-peptide values of <0.1 pmol/ml, consistent with clinically insignificant endogenous insulin secretion. There was no change in C-peptide response at 4 or 8 mo compared with baseline values, whether or not the patient's glucose control remained unchanged (CIT group) or significantly improved to near-normoglycemia (CSII group). In a subgroup of 34 patients at three centers, the 24-h mean glucose concentration was significantly lower in the CSII group compared with the CIT group at 4 mo (126 ± 10 versus 176 ± 14 mg/dl) and at 8 mo (121 ± 5 versus 183 ± 15 mg/dl) (P < 0.005). Although the 24-h mean serum free immunoreactive insulin levels were shown to be no different at baseline (27.4 ± 3.8 versus 26.2 ± 3.1 μU/ml) or after 4 mo (22.5 ± 3.2 versus 25.6 ± 3.2) or 8 mo (26.5 ± 3.4 versus 28.8 ± 3.4) of CIT or CSII therapy, respectively, the mean increase of free insulin concentrations in relation to the main meals was greater in the CSII group (P < 0.05). The mean serum free insulin levels achieved with both CIT and CSII were significantly greater than the 24-h mean free insulin level obtained in 12 normal subjects (12.2 ± 1.4 μU/ml) (P < 0.001).

Background— Among patients with severe aortic stenosis (AS) and preserved ejection fraction, those with low gradient (LG) and reduced stroke volume may have an adverse prognosis. We investigated the prognostic impact of stroke volume using the recently proposed flow-gradient classification. Methods and Results— We examined 1704 consecutive patients with severe AS (aortic valve area <1.0 cm 2 ) and preserved ejection fraction (≥50%) using 2-dimensional and Doppler echocardiography. Patients were stratified by stroke volume index (<35 mL/m 2 [low flow, LF] versus ≥35 mL/m 2 [normal flow, NF]) and aortic gradient (<40 mm Hg [LG] versus ≥40 mm Hg [high gradient, HG]) into 4 groups: NF/HG, NF/LG, LF/HG, and LF/LG. NF/LG (n=352, 21%), was associated with favorable survival with medical management (2-year estimate, 82% versus 67% in NF/HG; P <0.0001). LF/LG severe AS (n=53, 3%) was characterized by lower ejection fraction, more prevalent atrial fibrillation and heart failure, reduced arterial compliance, and reduced survival (2-year estimate, 60% versus 82% in NF/HG; P <0.001). In multivariable analysis, the LF/LG pattern was the strongest predictor of mortality (hazard ratio, 3.26; 95% confidence interval, 1.71–6.22; P <0.001 versus NF/LG). Aortic valve replacement was associated with a 69% mortality reduction (hazard ratio, 0.31; 95% confidence interval, 0.25–0.39; P <0.0001) in LF/LG and NF/HG, with no survival benefit associated with aortic valve replacement in NF/LG and LF/HG. Conclusions— NF/LG severe AS with preserved ejection fraction exhibits favorable survival with medical management, and the impact of aortic valve replacement on survival was neutral. LF/LG severe AS is characterized by a high prevalence of atrial fibrillation, heart failure, and reduced survival, and aortic valve replacement was associated with improved survival. These findings have implications for the evaluation and subsequent management of AS severity.

Objective: To summarize the pharmacology, development, and clinical application of sorafenib, a specific tyrosine kinase and vascular growth factor inhibitor, for the treatment of renal cell carcinoma (RCC). Data Sources: Clinical literature, including both primary studies and review articles, was obtained by searching MEDLINE (1966–May 2006), using the search terms BAY 43-9006, sorafenib, renal cell carcinoma, and tyrosine kinase inhibitor. Additional information was supplied by the manufacturer, Bayer HealthCare Pharmaceuticals. Study Selection and Data Extraction: Review articles, abstracts, and clinical studies related to sorafenib were analyzed. An evaluation of the research exploring sorafenib as a potential therapy for RCC was conducted. Relevant information was then selected and is reviewed in this article. Data Synthesis: Knowledge of the cellular abnormalities that can cause solid tumors has led to the development of medications that block these pathways. Sorafenib is an oral tyrosine kinase inhibitor that both blocks the Raf kinase pathway and inhibits vascular growth factors. Phase I and II trials have demonstrated that sorafenib has activity against RCC. Dermatologic reactions (rash, desquamation), fatigue, and hypertension have been the most commonly seen treatment-related adverse events. Sorafenib received FDA approval in December 2005 for treatment of advanced RCC. Conclusions: Sorafenib is a novel oral tyrosine kinase inhibitor effective in the treatment of RCC.

Objective: To report a case in which a young woman receiving medroxyprogesterone acetate injections developed deep vein thrombosis (DVT) after prolonged travel. Case Summary: An obese 27-year-old African American woman who had been receiving medroxyprogesterone acetate injections 150 mg intramuscularly every 3 months for 6 years experienced DVT after a 56-hour car ride. The patient's known risk factors for DVT included immobility, obesity (140 kg), and medroxyprogesterone acetate therapy. Family and personal history for thrombotic events were denied. Tests were performed after detection of the DVT to assess the patient for anticoagulation defects; results revealed an unidentified underlying protein S deficiency. All other test results were within normal limits. Discussion: Based on the Naranjo probability scale, it is possible that the DVT experienced by our patient was due to medroxyprogesterone acetate. Although she did have other risk factors for DVT, her underlying protein S deficiency was diagnosed after the thrombosis. Literature describing the relationship between the injectable form of contraception and thrombosis is limited. Therefore, this report reviews protein S deficiency, the relationship between oral contraceptives (OCs) and thrombosis, the influence of immobility on thrombosis development, and the clinical implications of evaluating patients for underlying inherited clotting abnormalities before initiating OCs. Conclusions: When considering whether to prescribe contraceptives, clinicians should assess the patient's risk factors for thrombosis, such as family or personal history. Although generally not recommended, prescreening tests may be considered if there is a positive family or personal history.