Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.

Intense stepped insulin therapy in NIDDM patients who have failed glycemic control on pharmacological therapy is effective in maintaining near-normal glycemic control for > 2 years without excessive severe hypoglycemia, weight gain, hypertension, or dyslipidemia. Cardiovascular event rates are high at this stage of NIDDM. A long-term prospective trial is needed to assess the risk-benefit ratio of intensified treatment of hyperglycemia in NIDDM patients requiring insulin.

Casein mRNA was isolated and partially purified from RNA extracts of rat lactating mammary glands and translated in a teterologous cell-free protein synthesizing system derived from wheat germ. Casein mRNA activity was assayed by immunoprecipitation using a specific antiserum prepared against a mixture of the purified rat caseins. Properties of rat casein mRNA were examined using a variety of sizing techniques, including chromatography on Sepharose 4B, sedimentation on sucrose gradients after heat denaturation, and electrophoresis on 2.5% agarose gels in 6 M urea. Casein mRNA activity was found in an 8-16S region after gradient centrifugation with the peak occurring at 10.5 S. In addition, the binding of rat casein mRNA to dT-cellulose was examined. Only 40% of the total casein mRNA activity was selectively retained. A partial purification of casein mRNA was accomplished by a combination of these sizing and affinity chromatography techniques. In the purified preparations casein mRNA activity comprises approximately 90% of the total mRNA activity. Characterization of this material by agarose gel electrophoresis revealed two main bands of RNA at approximately 12 and 16 S, both containing casein mRNA activity. These mRNAs were of the correct size to code for two of the principal rat caseins of approximately 25,000 and 42,000 molecular weights. Casein mRNA and total mRNA activities were then compared in total RNA extracts at various stages of normal mammary gland development in the rat, i.e. during pregnancy, lactation, and involution following weaning. A selective induction of casein mRNA activity compared to total mRNA activity was found to occur during pregnancy and lactation. Moreover, a selective loss of activity was also observed during mammary gland involution. A surprisingly high level of casein mRNA activity was found in RNA extracts from early and midpregnant mammary glands.

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A rapidly-labeled RNA fraction can be isolated from hen oviduct polysomes that has characteristics of the messenger RNA (mRNA) for the cell-specific protein, ovalbumin. This RNA, which sediments in the 8-17S region of sucrose gradients, possesses properties suggestive of the presence of a polyadenylic acid sequence and can be translated with fidelity in a cell-free protein synthesizing system derived from rabbit reticulocytes. The identity of the protein product as ovalbumin is confirmed by three methods, and translation of ovalbumin mRNA is shown to be dependent both on amount of exogenous mRNA and incubation time. Both rate and extent of ovalbumin synthesis is enhanced by the addition of a protein extract from ribosomes that contains peptide chain initiation factors. Finally, the presence of this specific mRNA is shown to be estrogen-dependent: it is induced by estrogen administration to immature chicks, disappears upon cessation of estrogen treatment, and can be reinduced by a single injection of estrogen to chicks that have been pretreated with estrogen and then withdrawn from the hormone.The cell-specific synthesis of ovalbumin serves as a characteristic biochemical marker for the estrogen-dependent differentiation of the chick oviduct (1-3). Studies to date have shown that estrogen induces changes in the pattern of synthesis of nuclear RNA before appearance of ovalbumin in the tissue (3-5). These observations are consistent with a hormone-regulated expression of the ovalbumin gene. However, the only direct assessment of messenger RNA (mRNA) is the ability of an RNA fraction to support the de novo synthesis of a specific protein in an in vitro translation system. Recently, rabbit reticulocyte lysate has been used successfully for this purpose by several laboratories, including our own (6-8). We now report data demonstrating that an 8-17S fraction of RNA isolated from oviduct polysomes contains the mRNA for ovalbumin that can be translated with fidelity in the reticulocyte system. Synthesis of ovalbumin in vitro shows a linear dependence on the amount of exogenous mRNA and is stimulated by addition of translation factors required for initiation of protein synthesis. Finally, the presence of the ovalbumin mRNA will be demonstrated to be directly dependent upon the degree of estrogen stimulation of the oviduct. MATERIALS AND METHODSAnimals. Immature chicks used in this study were Rhode Island Reds and were 7-days old at the beginning of the experiments. Young laying hens (5-6 months) were either Rhode Island Red or White Leghorns. For hormone experiments, immature chicks received daily subcutaneous injections of diethylstilbestrol (5 mg) in sesame oil. Precise injection protocols are described in the text.Isolation of Polysomes. Polyribosomes were isolated from chick oviduct as described. Fractionation of isolated polysomes on sucrose gradient has also been described (9, 10). For experiments with rapidly labeled polysomal RNA, oviduct was incubated in Eagle's minimal medium (1 ml/g) that contained [3H]...

NPH insulin given at bedtime in amounts sufficient to achieve a normal FPG level does not cause excessive or severe hypoglycemia and does lead to good glycemic and lipid control in NIDDM. Bedtime insulin therapy also is accompanied by improved insulin secretion and insulin sensitivity. We conclude that a single dose of insulin alone at bedtime merits consideration as a therapeutic strategy in patients with poorly controlled NIDDM.

The effects of the aldose-reductase inhibitor, tolrestat, on chronic symptomatic diabetic sensorimotor neuropathy were studied during a placebo-controlled, randomised, 52-week multicentre trial. Of the four tolrestat doses investigated, only the highest dose group, 200 mg once daily, showed subjective and objective benefit over baseline and placebo, and further analyses are confined to this group (n = 112) and placebo (n = 107). Painful and paraesthetic symptoms were analysed separately: improvement in paraesthetic symptoms were seen at one year (p = 0.04), though painful symptoms improved on both placebo and active therapies. Significant improvement in both tibial and peroneal motor nerve conduction velocities were seen at 52 weeks. Tolrestat 200 mg once daily was significantly better than placebo in producing concordant improvements in both motor nerve conduction velocities and paraesthetic symptom scores at 24 weeks (p = 0.01), 42 weeks (p = 0.01) and 52 weeks (p = 0.02). Long-term benefit [concordant improvement at 24 weeks maintained until 52 weeks] was seen in 28% of treated patients compared to 5% on placebo (p = 0.001). It is concluded that some sustained improvement in symptomatic diabetic neuropathy may be obtained following aldose-reductase inhibition with tolrestat 200 mg once daily.

OBJECTIVE -Microalbuminuria can reflect the progress of microvascular complications and may be predictive of macrovascular disease in type 2 diabetes. The effect of intensive glycemic control on microalbuminuria in patients in the U.S. who have had type 2 diabetes for several years has not previously been evaluated. RESEARCH DESIGN AND METHODS-We randomly assigned 153 male patients to either intensive treatment (INT) (goal HbA 1c 7.1%) or to standard treatment (ST) (goal HbA 1c 9.1%; P = 0.001), and data were obtained during a 2-year period. Mean duration of known diabetes was 8 years, mean age of the patients was 60 years, and patients were well matched at baseline. We obtained 3-h urine samples for each patient at baseline and annually and defined microalbuminuria as an albumin:creatinine ratio of 0.03-0.30. All patients were treated with insulin and received instructions regarding diet and exercise. Hypertension and dyslipidemia were treated with similar goals in each group.RESULTS -A total of 38% of patients had microalbuminuria at entry and were evenly assigned to both treatment groups. INT retarded the progression of microalbuminuria during the 2-year period: the changes in albumin:creatinine ratio from baseline to 2 years of INT versus ST were 0.045 vs. 0.141, respectively (P = 0.046). Retardation of progressive urinary albumin excretion was most pronounced in those patients who entered the study with microalbuminuria and were randomized to INT. Patients entering with microalbuminuria had a deterioration in creatinine clearance at 2 years regardless of the intensity of glycemic control. In the group entering without microalbuminuria, the subgroup receiving ST had a lower percentage of patients with a macrovascular event (17%) than the subgroup receiving INT (36%) (P = 0.03). Use of ACE inhibitors or calcium-channel blockers was similarly distributed among the groups.CONCLUSIONS -Intensive glycemic control retards microalbuminuria in patients who have had type 2 diabetes for several years but may not lessen the progressive deterioration of glomerular function. Increases in macrovascular event rates in the subgroup entering without albuminuria who received INT remain unexplained but could reflect early worsening, as observed with microvascular disease in the Diabetes Control and Complications Trial.