O’Brien, Peter C.

Insulin’s effect on the synthesis of liver proteins remains to be fully defined. Previous studies using various surrogate measures of amino acyl–tRNA have reported variable results of insulin’s effect on liver protein synthesis. We determined the effect of insulin with or without amino acid supplementation on the synthesis rates of liver proteins (tissue, albumin, and fibrinogen) using l-[1-13C]Leu as a tracer in 24 male miniature swine. In addition, we compared the isotopic enrichment of different precursors of liver proteins with that of amino acyl−tRNA using l-[1-13C]Leu and l-[15N]Phe as tracers. Although liver tissue fluid enrichment of [13C]Leu and [15N]Phe and that of plasma [13C]ketoisocaproatic acid (KIC) were very similar to that of tRNA, plasma isotopic enrichment of both Leu and Phe were substantially higher (P < 0.01) and VLDL apolipoprotein-B100 enrichment was lower (P < 0.01) than the respective amino acyl−tRNA enrichment. Plasma KIC enrichment most accurately predicted leucyl-tRNA enrichment, whereas plasma Leu enrichment was best correlated with that of tRNA. Neither insulin alone nor insulin plus amino acid infusion had an effect on liver tissue protein synthesis. In contrast, insulin alone decreased the albumin synthesis rate, and insulin with amino acids maintained the albumin synthesis rate. Insulin with or without amino acids inhibited the fibrinogen synthesis rate. These results, based on synthetic rates using amino acyl–tRNA, were consistent with those obtained using KIC or tissue fluid Leu or Phe as precursor pools. These studies demonstrated that plasma KIC enrichment is a convenient and reliable surrogate measure of leucyl-tRNA in liver. We also concluded that insulin has differential effects on the synthesis rates of liver proteins. Whereas insulin with or without amino acid supplement has no acute effect on the synthesis of liver tissue protein, insulin has a substantial inhibitory effect on fibrinogen synthesis. In contrast, insulin administration along with amino supplement is necessary to maintain albumin synthesis rate.

Ultralente has been used as the basal component of intensive insulin therapy programs. To determine the degree to which a single daily subcutaneous injection of beef ultralente provides stable basal insulin concentrations, plasma free insulin concentrations were measured in six insulin-dependent diabetic patients over a 40-h period. All short-acting insulin was withheld during this interval. Each patient had been maintained on a chronic ultralente based program before study. Little if any evidence of a temporal peak in plasma insulin concentrations was observed. Although considerable variation in plasma insulin concentrations was observed in one individual, beef ultralente provided relatively stable plasma insulin concentrations in the group as a whole. Beef ultralente appears to be a reasonable insulin preparation to use as the basal component in an intensive insulin therapy program.

OBJECTIVE—The objective of this study was to test whether monotone worsening of nerve function, attributable to diabetes, can be demonstrated before criteria for diabetic sensorimotor polyneuropathy (DSPN) have been met. Which nerve tests are best? RESEARCH DESIGN AND METHODS—From a prevalence cohort of 504 individuals in the Rochester Diabetic Neuropathy study (RDNS), we identified 238 individuals (group 1) who at first examination were without polyneuropathy (DSPN) by a sum score of the normal deviates (from percentiles) of five attributes of nerve conduction of the legs (i.e., their five nerve conduction normal deviate values were <97.5th percentile) and were followed longitudinally two or more times. Of these 238, 90 (group 2) were followed six or more times at yearly or biyearly intervals. We compared different nerve tests for the ones most sensitive and reliable in showing latent nerve dysfunction and monotone (the extent to which a variable measured repeatedly over time reveals a significant trend of worsening or improvement). RESULTS—In group 1 patients, the mean sum score of five attributes of nerve conduction (Σ 5 NC nds) at baseline was 1.08 and at the last examination (only patients with Σ 5 NC nds <97.5th percentile) was 3.63, markedly higher than that in healthy subjects (only of individuals with Σ 5 NC nds <97.5th percentile) (−0.12), indicating a subtle latent shift of nerve conduction tests toward abnormality. Serial evaluations of many individual and especially sum scores of nerve conduction tests in group 2 patients showed statistically significant worsening with time, even when nerve conduction tests were still well within normal limits. Neurologic signs also worsened but barely to significant levels; however, symptoms and quantitative sensation tests did not. Considering the composite score Σ 5 NC nds, 42 (of 90 group 2 patients) showed significant worsening, 22 were still without DSPN by nerve conduction test criteria, and some were even below the 50th percentile at the last evaluation. CONCLUSIONS—Subtle and latent functional worsening of nerve conduction can be demonstrated even before nerve conduction test criteria for DSPN have been met. For demonstrating monotone worsening, the order (from best to worst) of tests was: some composite scores of nerve conduction and individual attributes of nerve conduction. We did not show monotone worsening of symptoms or of quantitative sensation test results. In multivariate analysis of risk factors and their association with worsening Σ 5 NC nds, 24-h microalbuminuria (a marker of microvessel disease) was found to be a significant covariate, an indication that the asymptomatic alterations of nerve conduction are meaningful.

OBJECTIVE—The prevalence of autonomic symptoms and deficits in certain systems is known, but a comprehensive autonomic symptom profile in diabetes is not available. We aimed to estimate this using a laboratory evaluation of autonomic function and a validated self-report measure of autonomic symptoms in patients and matched control subjects from the population-based Rochester Diabetic Neuropathy Study. RESEARCH DESIGN AND METHODS—Participants included 231 patients with diabetes (type 1, n = 83; type 2, n = 148) and 245 healthy age-matched control subjects. We assessed symptoms using a validated self-report instrument (Autonomic Symptom Profile) and evaluated the severity and distribution of autonomic deficits (cardiovagal, sudomotor, adrenergic) with the objective, laboratory-based Composite Autonomic Severity Score (CASS). RESULTS—Autonomic symptoms were present more commonly in type 1 than in type 2 diabetes, with symptoms of orthostatic intolerance, secretomotor, urinary control, diarrhea, and sleep disturbance and pupillomotor, vasomotor, and erectile dysfunction significantly increased over healthy control subjects in type 2 diabetic patients. The prevalence of autonomic impairment was 54% in type 1 and 73% in type 2 diabetic patients. Severity of autonomic failure was mild overall (mean CASS 2.3; maximum 10), with orthostatic hypotension occurring in 8.4 and 7.4% of type 1 and 2 diabetic patients, respectively. Fourteen percent of patients had a CASS ≥5, indicating moderate to severe generalized autonomic failure. The correlation of symptoms with autonomic deficits (CASS) was better in type 1 than type 2 diabetic subjects and was weak overall. CONCLUSIONS—These findings indicate that autonomic symptoms and deficits are common in diabetes, but mild in severity, and that the correlation between symptom scores and deficits is overall weak in mild diabetic neuropathy, emphasizing the need to separately evaluate autonomic symptoms.

OBJECTIVE: To test quantitative sensation testing (QST) patterns of hypoesthesia and hyperalgesia as indicators of diabetic polyneuropathy (DPN) and its severity RESEARCH DESIGN AND METHODS: We used Computer-Assisted Sensory Examination IV; characterized the QST results of the foot of each patient in three diabetic cohorts (approximately 1,500 patients) as hyperesthetic (< or = 2.5th percentile), low-normal (2.5th-50th percentiles), high-normal (50th-97.5th percentiles), or hypoesthetic (> or = 97.5th percentile); and tested associations with symptoms, impairments, and test abnormalities. RESULTS: Overall neuropathic impairment was most severe in the pancreas-renal transplant and nerve growth factor cohorts, but it was much less severe in the population-based Rochester Diabetic Neuropathy Study (RDNS) cohort. The frequency distribution of sensory abnormalities mirrored this difference. When the QST spectra of diabetic cohorts were compared with those of the control subject cohort for vibration and cooling sensations, the only abnormality observed was hypoesthesia, which was expressed as an increased number of subjects with values at or above the 97.5th percentile or by an increased percentage of cases with high-normal values. Symptoms and impairments of DPN were significantly more frequent in the subjects with values at or above the 97.5th percentile than in the subjects whose values were between the 50th and 97.5th percentiles. For heat pain (HP) sensation thresholds (intermediate pain severity [HP:5], pain threshold [HP:0.5], and pain-stimulus response slope [HP:5-0.5]), an increased frequency of both hypoalgesia and hyperalgesia was observed (especially in the RDNS cohort). Steeper pain-stimulus response slopes were significantly associated with sensory symptoms, including severity of pain. CONCLUSIONS: 1) Decreased vibratory sensation (hypoesthesia) appears to be characteristic of mild DPN, whereas panmodality hypoesthesia is characteristic of severe DPN. 2) A shift of vibratory and cold detection thresholds (and also of attributes of nerve conduction and a measure of autonomic dysfunction) from low-normal (2.5th-50th percentiles) to high-normal (50th-97.5th percentiles) appears to precede overt expression of DPN and to thereby provide evidence of subclinical abnormality 3) Heat stimulus-induced hyperesthesia (low thresholds) occurs especially in mild DPN, and, because it correlates with DPN symptoms and impairments, it must be attributed to hyperalgesia rather than to supersensitivity Therefore, hypoalgesia or hyperalgesia may be an indicator of early DPN.

OBJECTIVE: This study investigates temporal trends in the prevalence and incidence of persistent proteinuria among people with adult-onset diabetes (age > or =40 years). RESEARCH DESIGN AND METHODS: The complete community-based medical records of all Rochester, Minnesota, residents with a diagnosis of diabetes or diabetes-like condition from 1945 through 1989 were reviewed to determine whether they met National Diabetes Data Group (NDDG) criteria. All confirmed diabetes cases residing in Rochester on 1 January 1970 (n = 446), 1980 (n = 647), and/or 1990 (n = 940) were identified. The medical records of these prevalence cases were reviewed from the time of the first laboratory urinalysis value to the last visit, death, or 1 April 1992 (whichever came first) for evidence of persistent proteinuria (two consecutive urinalyses positive for protein, with no subsequent negative values). Similarly, the medical records of all 1970-1989 diabetes incidence cases (n = 1,252) were reviewed to investigate temporal changes in 1) the likelihood of having persistent proteinuria before the date NDDG criteria was met, i.e., baseline; 2) the risk of persistent proteinuria after baseline; and 3) the relative risk of mortality associated with persistent proteinuria. RESULTS: The proportion of diabetes prevalence cases with persistent proteinuria on or before the prevalence date declined from 20% in 1970 to 11% in 1980 and 8% in 1990. Among the 1970-1989 diabetes incidence cases, 77 (6%) had persistent proteinuria on or before baseline; the adjusted odds declined by 50% with each 10-year increase in baseline calendar year (P<0.001). Among individuals free of persistent proteinuria at baseline, 136 subsequently developed persistent proteinuria; the estimated 20-year cumulative incidence was 41% (95% CI 31-59); the adjusted risk did not differ as a function of baseline calendar year. Survival of individuals with persistent proteinuria relative to those without was reduced but did not differ by baseline calendar year. CONCLUSIONS: The prevalence of persistent proteinuria among people with adult-onset diabetes in Rochester, Minnesota, declined 60% between 1970 and 1990. The decline appears because of a decrease in the proportion of diabetes incidence cases with persistent proteinuria before baseline rather than secular declines in the risk of persistent proteinuria after baseline or secular increases in the risk of mortality associated with persistent proteinuria. Similarity over time in age and fasting glucose at baseline, and at prevalence dates, is evidence that earlier detection of diabetes is not the sole explanation for the decline.

OBJECTIVE: Chronic hyperglycemia relates to the occurrence of diabetic polyneuropathy (DPN), but has not yet been shown to relate to its overall severity In addition, the degree and duration of hyperglycemia, which measure of chronic hyperglycemia is most predictive of defined levels of severity of DPN, and which other putative risk factors are involved remain unknown. RESEARCH DESIGN AND METHODS: In a longitudinal study of 264 diabetic individuals in Rochester, MN, risk factors and other diabetic complications assessed at regular intervals during an average of approximately 7 years were tested for their association with a composite score of severity of DPN at the last examination. RESULTS: In multivariate analysis, diabetic retinopathy severity level (at last examination), mean ln(24-h proteinuria x duration of diabetes), and mean GHb were the main covariates for severity of DPN (R2 = 0.33). Excluding markers of microvessel and macrovessel disease, the independent risk factors were mean In(GHb x duration of diabetes), GHb, and type of diabetes (R2 = 0.23). CONCLUSIONS: We found that diabetic microvessel disease, chronic hyperglycemia exposure, and type of diabetes are associated with severity of DPN, and we believe these factors are implicated in its cause. Each of the five markers of microvessel disease was a strong covariate for severity of DPN. Mean GHb predicts severity of DPN better than duration of diabetes, and the latter predicts severity of DPN better than mean fasting plasma glucose. Knowing the severity of microvessel disease, the degree of chronic hyperglycemia exposure, and the type of diabetes provides useful information to evaluate whether a coexisting polyneuropathy and its severity is probably due to diabetes.

OBJECTIVE Using a novel minimally invasive (≤ 1.4 mm) technique to sample minuscule (0.5 microliter) amounts of dermal interstitial fluid (ISF), we assessed the accuracy of its glucose concentrations in predicting concurrently measured venous plasma and capillary plasma glucose concentrations. RESEARCH DESIGN AND METHODS A total of 67 adult (37 male and 30 female) volunteers (57 with and 10 without diabetes) with venous plasma glucose levels from 1.6 to 28.4 mmol/l underwent forearm ISF, antecubetal venous, and fingertip capillary sampling. RESULTS Rank correlations were 0.974 for ISF 1 vs. 2, 0.954 for ISF vs. venous, 0.935 for ISF vs. capillary, and 0.987 for venous vs. capillary. Median absolute differences were 0.53 mmol/l for ISF 1 vs. 2, 1.33 mmol/l for ISF vs. venous, 1.06 mmol/l for ISF vs. capillary, and 0.56 mmol/l for capillary vs. venous. Equations expressing ISF glucose as a function of venous and capillary glucose and equations expressing capillary glucose as a function of venous glucose had slopes of 0.995, 0.936, and 1.021, respectively (none significantly different from unity), and intercepts of 1.03 mmol/l (P = 0.024), 0.94 mmol/l (P = 0.131), and 0.56 mmol/l (P = 0.041), respectively. Error grid analysis of ISF vs. venous glucose and of capillary vs. venous glucose showed that 97% of the measurements fell within grids A and B. CONCLUSIONS Dermal ISF sampling is a bloodless minimally invasive technique that provides a medium for glucose measurement, the concentrations of which closely reflect ambient glycemia to a degree comparable with that of capillary glucose measurements.

OBJECTIVE To evaluate both the concordance in the classification of diabetes by clinical and C-peptide criteria and, prospectively, the consistency of the classification by C-peptide. RESEARCH DESIGN AND METHODS Individuals with diabetes who were enlisted in the prospective epidemiological study of diabetic neuropathy (Rochester Diabetic Neuropathy Study [RDNS]) were classified clinically by National Diabetes Data Group (NDDG) criteria to IDDM and NIDDM at entry to the study. In addition, C-peptide response to 1 mg glucagon was measured at entry for the classification to IDDM (basal C-peptide, < 0.17 pmol/ml; increment above basal, < 0.07 pmol/ml) and NIDDM (all other responses) and for concordance with the clinical classification made. The consistency of the C-peptide response was assessed every 2 years for up to 8 years. RESULTS Among 346 individuals with diabetes, 84 were classified as IDDM and 262 as NIDDM by clinical algorithm. COncordance with the C-peptide response occurred in 89% of the patients and remained consistent during 8 years of follow-up. Among the 37 patients with discordant clinical and C-peptide classification, those considered clinically to have NIDDM had a consistent IDDM C-peptide response during follow-up, and most of those considered to have IDDM clinically eventually showed an IDDM C-peptide response during follow-up. CONCLUSIONS Clinical criteria for the classification of diabetes are highly correlated with the assessment of insulin secretory reserve. A small number of individuals considered to have NIDDM clinically or by C-peptide have or develop an IDDM peptide response.

OBJECTIVE Despite widespread acceptance of continuous insulin infusion (CII) over bolus insulin injection (BII) for treatment of diabetic ketoacidosis (DKA), there are no population-based studies demonstrating whether CII has resulted in lower morbidity and mortality. RESEARCH DESIGN AND METHODS We addressed this issue using a provider-linked database and retrospectively reviewing the complete medical records of all incidence cases of diabetes among Rochester, Minnesota, residents from 1950 to 1989 with a discharge diagnosis of DKA. This population-based study describes the consequences of the widespread change in treatment modality outside the confines of a controlled clinical trial. RESULTS Among the diabetes incident cohort, there were 59 subjects with confirmed first episodes of DKA during 1950-1992; 29 of 30 subjects treated with BII occurred before 1970. All 29 CII cases occurred between 1976 and 1992. Sex, etiology, diabetes duration, and age at DKA were similar for the two groups. The proportion of obese individuals (BII = 2/28, CII = 8/21; P = 0.01) differed between groups. The CII group exhibited higher glucose values (BII = 24.9 ± 8.5 mmol/l, CII = 37.1 ± 15.1 mmol/l; P = 0.002) and lower bicarbonate values (BII = 7.7 ± 3.0 nmol/l, CII = 6.2 ± 2.9 nmol/l; P = 0.04) upon admission. The mean quantity of insulin administered was higher in the BII group than in the CII group (179 ± 140 and 99 ± 70 U, P < 0.006). The outcome of hypoglycemia occurred more frequently in the BII group than in the CII group (BII = 8/30, CII = 1/29; P = 0.03). The proportion with hypokalemia, neurological deficit, myocardial arrhythmia, or mortality did not differ significantly between groups. CONCLUSIONS Our findings suggest the introduction of CII was accompanied by a decreased incidence of hypoglycemia.