OBJECTIVE

The etiology of altered sensorium in diabetic ketoacidosis (DKA) remains unclear. Therefore, we sought to determine the origin of depressed consciousness in DKA.

RESEARCH DESIGN AND METHODS

We analyzed retrospectively clinical and biochemical data of DKA patients admitted in a community teaching hospital.

RESULTS

We recorded 216 cases, 21% of which occurred in subjects with type 2 diabetes. Mean serum osmolality and pH were 304 ± 31.6 mOsm/kg and 7.14 ± 0.15, respectively. Acidosis emerged as the prime determinant of altered sensorium, but hyperosmolarity played a synergistic role in patients with severe acidosis to precipitate depressed sensorium (odds ratio 2.87). Combination of severe acidosis and hyperosmolarity predicted altered consciousness with 61% sensitivity and 87% specificity. Mortality occurred in 0.9% of the cases.

CONCLUSIONS

Acidosis was independently associated with altered sensorium, but hyperosmolarity and serum “ketone” levels were not. Combination of hyperosmolarity and acidosis predicted altered sensorium with good sensitivity and specificity.

OBJECTIVE—The purpose of this study was to assess the efficacy of an insulin priming dose with a continuous insulin infusion versus two continuous infusions without a priming dose.

RESEARCH DESIGN AND METHODS—This prospective randomized protocol used three insulin therapy methods: 1) load group using a priming dose of 0.07 units of regular insulin per kg body weight followed by a dose of 0.07 unit · kg−1 · h−1 i.v. in 12 patients with diabetic ketoacidosis (DKA); 2) no load group using an infusion of regular insulin of 0.07 unit · kg body weight−1 · h−1 without a loading dose in 12 patients with DKA, and 3) twice no load group using an infusion of regular insulin of 0.14 · kg−1 · h−1 without a loading dose in 13 patients with DKA. Outcome was based on the effects of insulin therapy on biochemical and hormonal changes during treatment and recovery of DKA.

RESULTS—The load group reached a peak in free insulin value (460 μU/ml) within 5 min and plateaued at 88 μU/ml in 60 min. The twice no load group reached a peak (200 μU/ml) at 45 min. The no load group reached a peak (60 μU/ml) in 60–120 min. Five patients in the no load group required supplemental insulin doses to decrease initial glucose levels by 10%; patients in the twice no load and load groups did not. Except for these differences, times to reach glucose ≤250 mg/dl, pH ≥7.3, and HCO3− ≥15 mEq/l did not differ significantly among the three groups.

CONCLUSIONS—A priming dose in low-dose insulin therapy in patients with DKA is unnecessary if an adequate dose of regular insulin of 0.14 unit · kg body weight−1 · h−1 (about 10 units/h in a 70-kg patient) is given.

OBJECTIVE

Rates of severe obesity (BMI ≥40 kg/m2) are on the rise, and effective treatment options are needed. We examined the effect of an intensive lifestyle intervention (ILI) on weight loss, cardiovascular disease (CVD) risk, and program adherence in participants with type 2 diabetes who were severely obese compared with overweight (BMI 25 to <30 kg/m2), class I (BMI 30 to <35 kg/m2), and class II (BMI 35 to <40 kg/m2) obese participants.

RESEARCH DESIGN AND METHODS

Participants in the Action for Health in Diabetes (Look AHEAD) trial were randomly assigned to ILI or diabetes support and education (DSE). DSE participants received a less intense educational intervention, whereas ILI participants received an intensive behavioral treatment to increase physical activity (PA) and reduce caloric intake. This article focuses on the 2,503 ILI participants (age 58.6 ± 6.8 years).

RESULTS

At 1 year, severely obese participants in the ILI group lost −9.04 ± 7.6% of initial body weight, which was significantly greater (P < 0.05) than ILI participants who were overweight (−7.43 ± 5.6%) and comparable to class I (−8.72 ± 6.4%) and class II obese (−8.64 ± 7.4%) participants. All BMI groups had comparable improvements in fitness, PA, LDL cholesterol, triglycerides, blood pressure, fasting glucose, and HbA1c at 1 year. ILI treatment session attendance was excellent and did not differ among weight categories (severe obese 80% vs. others 83%; P = 0.43).

CONCLUSIONS

Severely obese participants in the ILI group had similar adherence, percentage of weight loss, and improvement in CVD risk compared with less obese participants. Behavioral weight loss programs should be considered an effective option for this population.

OBJECTIVE

Most patients with ketosis-prone type 2 diabetes (KPD) discontinue insulin therapy and remain in near-normoglycemic remission. The aim of this study was to determine the effect of glucotoxicity on β-cell function during remission in obese patients with KPD.

RESEARCH DESIGN AND METHODS

Age- and BMI-matched obese African Americans with a history of KPD (n = 8), severe hyperglycemia but without ketosis (ketosis-resistant type 2 diabetes, n = 7), and obese control subjects (n = 13) underwent intravenous infusion of 10% dextrose at a rate of 200 mg per m2/min for 20 h. β-Cell function was assessed by changes in insulin and C-peptide concentrations during dextrose infusion and by changes in acute insulin response (AIR) and first-phase insulin release (FPIR) to arginine stimulation before and after dextrose infusion.

RESULTS

The mean ± SD time to discontinue insulin therapy was 7.1 ± 1.7 weeks in KPD and 9.6 ± 2.3 weeks in ketosis-resistant type 2 diabetes (NS). During a 20-h dextrose infusion, changes in insulin, C-peptide, and the C-peptide–to–glucose ratio were similar among diabetic and control groups. During dextrose infusion, subjects with ketosis-resistant type 2 diabetes had greater areas under the curve for blood glucose than subjects with KPD and control subjects (P < 0.05). The AIR and FPIR to arginine stimulation as well as glucose potentiation to arginine assessed before and after dextrose infusion were not different among the study groups.

CONCLUSIONS

Near-normoglycemia remission in obese African American patients with KPD and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. At near-normoglycemia remission, patients with KPD displayed a pattern of insulin secretion similar to that of patients with ketosis-resistant type 2 diabetes and obese nondiabetic subjects.

OBJECTIVE

Over half of newly diagnosed obese African Americans with diabetic ketoacidosis (DKA) discontinue insulin therapy and go through a period of near-normoglycemia remission. This subtype of diabetes is known as ketosis-prone type 2 diabetes (KPDM).

RESEARCH DESIGN AND METHODS

To investigate the role of lipotoxicity on β-cell function, eight obese African Americans with KPDM, eight obese subjects with type 2 diabetes with severe hyperglycemia without ketosis (ketosis-resistant type 2 diabetes), and nine nondiabetic obese control subjects underwent intravenous infusion of 20% intralipid at 40 ml/h for 48 h. β-Cell function was assessed by changes in insulin and C-peptide concentration during infusions and by changes in acute insulin response to arginine stimulation (AIRarg) before and after lipid infusion.

RESULTS

The mean time to discontinue insulin therapy was 11.0 ± 8.0 weeks in KPDM and 9.6 ± 2.2 weeks in ketosis-resistant type 2 diabetes (P = NS). At remission, KPDM and ketosis-resistant type 2 diabetes had similar glucose (94 ± 14 vs. 109 ± 20 mg/dl), A1C (5.7 ± 0.4 vs. 6.3 ± 1.1%), and baseline AIRarg response (34.8 ± 30 vs. 64 ± 69 μU/ml). P = NS despite a fourfold increase in free fatty acid (FFA) levels (0.4 ± 0.3 to 1.8 ± 1.1 mmol/l, P < 0.01) during the 48-h intralipid infusion; the response to AIRarg stimulation, as well as changes in insulin and C-peptide levels, were similar among obese patients with KPDM, patients with ketosis-resistant type 2 diabetes, and nondiabetic control subjects.

CONCLUSIONS

Near-normoglycemia remission in obese African American patients with KPDM and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. A high FFA level by intralipid infusion for 48 h was not associated with β-cell decompensation (lipotoxicity) in KPDM patients.

Background

Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.

Methods/Design

602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.

Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.

Conclusion

ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.

Trial Registration

clinical trials.gov identifier: NCT00220961

The renal handling of immunoreactive insulin was studied in the isolated perfused normothermic rat kidney to determine (a) the relative contributions of glomerular clearance and peritubular clearance to the renal clearance of insulin under different conditions, (b) what metabolic factors influence the ability of tubular cells to remove insulin from the glomerular filtrate and the peritubular circulation, and (c) whether the same factors influence the luminal and contraluminal uptake of insulin.

In control kidneys the organ clearance of insulin (OCi) was 974±63 μl/min (SEM), of which a maximum of 46% could theoretically be accounted for by filtration. OCi was not altered by fasting, lack of exogenous fuel (glucose), or the addition of cyanide. The glomerular filtration rate did not correlate with the OCi, but there was a significant (P < 0.001) negative correlation (r = −0.828) between the peritubular clearance and glomerular filtration rate. Both N-ethylmaleimide and cold (10°C) reduced the rate of insulin removal. Fractional excretion of filtered insulin (9.7±1.7% in controls) was not significantly altered by fasting or perfusing without glucose. In contrast, KCN increased fractional excretion of insulin to 41.9±3.7% whereas cold increased fractional excretion to 69.0±3.3%.

This study indicates that renal tubular cells remove insulin from the tubular lumen and the peritubular compartment. Furthermore, the data suggest that insulin removal by tubular cells is a temperature-sensitive process consisting of two different systems. The system associated with the luminal aspect of the cell appears to be dependent on oxidative metabolism, whereas the system associated with the contraluminal aspects of the cell appears to be independent thereof. Under several circumstances when the glomerular clearance of insulin falls thereby reducing the amount of insulin absorbed by the luminal aspect of the cell, contraluminal uptake increases, and a constant rate of insulin removal is maintained by the kidney.

A method has been described for the direct measurement of proinsulin in human plasma. The method makes use of an insulin-degrading enzyme designated “insulin-specific protease (ISP)”, which is obtained from rat skeletal muscle. Under the conditions used, this enzyme rapidly degrades insulin and insulin-like polypeptides to nonimmunoassayable components, whereas proinsulin and proinsulin cleaved at position B54,55 are not appreciably affected. The incubation of plasma with ISP results in the disappearance of insulin, but not proinsulin, as demonstrated by column chromatography. Immunoassay of the plasma, therefore, before and after incubation, determines the values for the total immunoreactive substance (TIR) and for immunoreactive proinsulin (IRP), respectively. The values obtained for proinsulin levels are reproducible and compare closely with the more complicated column fractionation methods.

Proinsulin responses were studied in four normal subjects and one patient with an insulinoma after a glucose load. Fasting proinsulin levels varied widely in the normal subjects, and the levels rose more slowly than TIR levels after glucose. IRP levels in the patient with an insulinoma were very high and fell to normal after removal of the tumor.

The ISP method, therefore, appears to be suitable for the direct, accurate, and rapid determination of proinsulin and proinsulin-like materials in human plasma.

The recently discovered hormone precursors, pork and beef proinsulins, their respective connecting peptides, and beef proinsulin intermediates have been compared to insulin in their ability to stimulate the conversion of glucose-U-14C to 14CO2 and lipids in isolated fat cells. The concentrations of beef and pork proinsulins required to achieve the same biological effect were respectively, 15 and 10 times that of insulin. Beef proinsulin intermediates required only 2.6 times the concentration of insulin for the same effect. Pork and beef connecting peptides in high or low concentrations alone or in combination with proinsulin, insulin, or proinsulin intermediates showed no biological effect on the isolated fat cell system. The insulin-like activity of beef and pork proinsulins on the isolated fat cell system was not abolished with pancreatic trypsin or kallikrein inhibitors. Pork insulin antiserum inhibited the biological activity of pork insulin and proinsulin as well as that of beef insulin or proinsulin. Pork proinsulin antiserum also inhibited the insulin-like activity of both pork insulin and proinsulin. By the radioimmunoassay method, pork insulin antiserum bound only ¼ to [unk] as much proinsulin as insulin. Beef proinsulin intermediates, on the other hand, were found to react with the pork insulin antiserum to an extent nearly equal to that of insulin. These data suggest that (a) proinsulin exhibits its effect on the isolated fat cells independent of its conversion to insulin, (b) connecting peptides have no biological effect under present experimental conditions, and (c) in comparison to insulin, immunological reactivity of proinsulin is greater than its biological activity using our pork insulin antiserum; thus, the comparison of antibody specificity with the fat cell receptor specificity suggests that the biological site of action is different from the immunologic site.

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Objective

The study objective was to examine the association between menopause status and diabetes risk among women with glucose intolerance and to determine if menopausal status modifies response to diabetes prevention interventions.

Methods

The study population included women in premenopause (n=708), natural postmenopause (n=328), and bilateral oophorectomy (n=201) in the Diabetes Prevention Program (DPP), a randomized placebo-controlled trial of lifestyle intervention and metformin among glucose intolerant adults. Associations between menopause and diabetes risk were evaluated using Cox proportional hazard models that adjusted for demographic variables (age, race/ethnicity, family history of diabetes, history of gestational diabetes mellitus), waist circumference, insulin resistance and corrected insulin response. Similar models were constructed after stratification by menopause type and hormone therapy (HT) use.

Results

After adjustment for age, there was no association between natural menopause or bilateral oophorectomy and diabetes risk. Differences by study arm were observed in women who reported bilateral oophorectomy. In the lifestyle arm, women with bilateral oophorectomy had a lower adjusted hazard for diabetes (HR 0.19, 95% CI 0.04, 0.94), although observations were too few to determine if this was independent of HT use. No significant differences were seen in the metformin (HR 1.29, 95% CI 0.63, 2.64) or placebo arms (HR 1.37, 95% CI 0.74, 2.55).

Conclusions

Among women at high-risk for diabetes, natural menopause was not associated with diabetes risk and did not affect response to diabetes prevention interventions. In the lifestyle intervention, bilateral oophorectomy was associated with decreased diabetes risk.