Prolactin and beta-endorphin responses to hypoglycemia are reduced in well-controlled insulin-dependent diabetes mellitus

Several pituitary hormones, including corticotropin (ACTH), growth hormone (GH), prolactin, and beta-endorphin (but not thyrotropin, follicle-stimulating hormone, or luteinizing hormone), are released in response to hypoglycemia in normal subjects. In patients with insulin-dependent diabetes mellitus (IDDM), the degree of glycemic control is known to alter ACTH and GH responses to hypoglycemia. The current study was performed to examine the effect of glycemic control on prolactin and beta-endorphin responses to hypoglycemia in subjects with IDDM. We performed 3-hour stopped hypoglycemic-hyperinsulinemic clamp studies (12 pmol/kg/min) during which plasma glucose was decreased from 5.0 mmol/L to 2.2 mmol/L in steps of 0.6 mmol/L every 30 minutes in 20 subjects with uncomplicated IDDM (12 males and eight females; age, 26 +/- 2 years; IDDM duration, 10 +/- 1 years; body mass index, 23.6 +/- 0.6 kg/m2) and 10 healthy subjects (five males and five females aged 30 +/- 1 years). The 10 diabetic subjects in good glycemic control (mean hemoglobin A1 [HbA1], 7.5% +/- 0.3%; normal range, 5.4% to 7.4%) were compared with the 10 poorly controlled patients (mean HbA1, 12.6% +/- 0.5%; P < .001 v well-controlled diabetic group). During hypoglycemia, prolactin levels in the well-controlled diabetic group did not change (7 +/- 1 microgram/L at plasma glucose 5.0 mmol/L to 9 +/- 2 micrograms/L at plasma glucose 2.2 mmol/L), whereas prolactin levels increased markedly in the poorly controlled diabetic group (7 +/- 2 micrograms/L to 44 +/- 17 micrograms/L) and healthy volunteers (12 +/- 2 micrograms/L to 60 +/- 19 micrograms/L, P < .05 between IDDM groups). The plasma glucose threshold required for stimulation of prolactin secretion was 2.2 +/- 0.1 mmol/L in well-controlled IDDM, 3.0 +/- 0.4 mmol/L in poorly controlled IDDM, and 2.4 +/- 0.1 mmol/L in healthy subjects (P < .05 between IDDM groups). Responses in males and females were similar. The increase in beta-endorphin levels was also attenuated in well-controlled IDDM patients (4 +/- 1 pmol/L at plasma glucose 5.0 mmol/L to 11 +/- 4 pmol/L at plasma glucose 2.2 mmol/L) versus poorly controlled IDDM patients (5 +/- 1 pmol/L to 26 +/- 7 pmol/L) and healthy subjects (8 +/- 1 pmol/L to 56 +/- 13 pmol/L). The plasma glucose threshold required for stimulation of beta-endorphin release was again lower in well-controlled IDDM versus poorly controlled IDDM patients (2.2 +/- 0.1 v 3.0 +/- 0.3 mmol/L) and healthy subjects (2.5 +/- 0.4 mmol/L, P < .05 between IDDM groups). In conclusion, prolactin and beta-endorphin responses to a standardized hypoglycemic stimulus (plasma glucose, 2.2 mmol/L) are reduced and plasma glucose levels required to stimulate release of prolactin and beta-endorphin are lower in well-controlled IDDM compared with poorly controlled IDDM and healthy subjects. Thus, stress hormones not previously considered to have a primary role in plasma glucose recovery from hypoglycemia are affected by glycemic control, suggesting a more generalized alteration of hypothalamic-pituitary responses to hypoglycemia in IDDM patients with strict glycemic control.     

Optimization of glycemic control by insulin therapy decreases the proportion of small dense LDL particles in diabetic patients

Small dense LDL particles (B phenotype) are considered to be more atherogenic than large buoyant LDL particles. The influence of glycemic control on LDL particle size and density is still under debate. The aim of this study was to determine LDL subfraction phenotype in both IDDM and NIDDM patients in poor glycemic control compared with that of respective matched control groups. In addition, we evaluated the effect of a 3-month period of optimized glycemic control on this parameter. Thirty-seven IDDM patients and 33 NIDDM patients, together with two respective age-, sex-, and BMI-matched control groups were studied. Non-A phenotype prevalence in IDDM patients before (19%) and after blood glucose optimization (11%) was similar to that of their control group (12%). However, NIDDM patients displayed a higher proportion of the non-A phenotype (51%) than did the control group (28%), but it became closer (30%, P < 0.05) after glycemic control improved. All subjects with non-A phenotype that changed to A phenotype showed triglyceride levels below 1.63 mmol/l and a greater decrease in HbA1c than did subjects whose phenotype did not change (4.9 +/- 1.5 vs. 3.1 +/- 1.4%, P < 0.05). A higher proportion of small dense LDL was observed in NIDDM women than in nondiabetic women (LDL5 10.0 +/- 4.8 vs. 6.3 +/- 1.5%, LDL6 6.1 +/- 2.2 vs. 4.2 +/- 0.8%, P < 0.05) during both stages of glycemic control, but no differences were observed between NIDDM and nondiabetic men. In conclusion, these findings provide new evidence for the relevance of near-normal glycemic control in the prevention of macrovascular disease and could contribute to an explanation of the loss of protection for cardiovascular disease in diabetic women.     

Women with insulin-dependent diabetes mellitus (IDDM) complicated by eating disorders are at risk for exacerbated alterations in lipid metabolism

OBJECTIVE: To examine lipid parameters that are affected in women with insulin-dependent diabetes mellitus (IDDM) who engaged in disordered eating behaviours. DESIGN: Randomized, unmatched. SETTING: Tertiary care. SUBJECTS: Ninety women (18-46 y) with IDDM. INTERVENTIONS: Classification of subjects based on severity of eating disorder: clinical (n = 14), subclinical (n = 13) and control (n = 63). Blood was analysed for glycosylated haemoglobin (HbA1c) and serum for triglycerides and cholesterol. Carotenoid and tocopherol concentrations were analysed by high performance liquid chromatography (HPLC). Dietary intake was assessed by the National Cancer Institute food frequency questionnaire. RESULTS: HbA1c was significantly increased im women demonstrating clinical and subclinical symptoms compared to control (10.4 +/- 2.6, 10.0 +/- 1.5 and 8.3 +/- 1.6%, respectively, P < 0.05). Triglycerides concentrations were significantly increased in women with subclinical eating disorders compared to controls. In women who intentionally omitted or reduced insulin, triglyceride cholesterol and HbA1c were significantly increased compared to controls. Women with IDDM and eating disorders who exhibited bulimic behaviours consumed significantly more energy, total fat and cholesterol compared to controls and women with eating disorders who were restrained eaters. CONCLUSION: While IDDM is known to perturb lipid metabolism, these data demonstrate that eating disorders, in combination with IDDM, results in additional alterations in lipid metabolism.     

Long-term glycemic control has a nonlinear association to the frequency of background retinopathy in adolescents with diabetes. Follow-up of the Berlin Retinopathy Study

OBJECTIVE: To assess the influence of long-term glycemic control on the development of background retinopathy in adolescents followed longitudinally from the onset of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: Repeated retinal fluorescein angiographies, in intervals of 1-2 years, were evaluated prospectively in 346 patients (190 males, 156 females; 19.8 [8.8-35.4] years of age; diabetes duration of 10.4 [1.1-27.4] years at their latest eye examination, median [range]). The influences of long-term HbA1c (mean of 18 [1-95] determinations per person) and microalbuminuria (> or = 2 of > or = 3 measurements > or = 15 micrograms/min x 1.73 m2) were studied by multiple linear regression, life-table analysis, and trend analyses. RESULTS: The rate of background retinopathy per 100 patient-years increased with poorer glycemic control from 0.7 (long-term HbA1c < 7% to 7.3 (HbA1c > 11%) following an exponential function. Life-table analysis after subdivision in HbA1c quartiles of equal sizes (HbA1c < 8, 8-9, 9-10, and > 10%) revealed an individual median expectation of background retinopathy after more than 25, 16.2, 12.7, or 12.0 years of diabetes, respectively. However, significant differences were found only between 8-9% and 9-10%, calculated either as prevalence, life-table analysis, or relative incidence, thus suggesting that a threshold model may also fit the data. After 12 years of diabetes, < 25% of those patients exhibiting microalbuminuria (n = 18) were expected to be free from retinopathy compared with 81% of those with normoalbuminuria (n = 86). CONCLUSIONS: Two statistical models are appropriate to explain the relationship between glycemic control and risk for background retinopathy: 1) a continuous exponential relationship as described by the DCCT or 2) the presence of a threshold HbA1c level at 9%. Thus, diabetes treatment in children should aim at long-term HbA1c levels < 9.0%, but every progress closer to normal may further reduce the risk.     

Endothelium-dependent and -independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus

Vascular complications in diabetes mellitus are associated with endothelial dysfunction. Whether endothelium-dependent vasodilation is impaired in normoalbuminuric patients with insulin-dependent diabetes mellitus (IDDM) is controversial. Using a noninvasive echo-Doppler method, we investigated endothelium-dependent and endothelium-independent vasodilation in the brachial artery of IDDM patients. There were 52 normoalbuminuric and normotensive patients with IDDM (aged 31.9 +/- 9.8 years; diabetes duration, 14.9 +/- 7.9 years; glycated hemoglobin, 7.9 +/- 1.2%) and 52 healthy control group (C) subjects comparable for age and sex studied. Brachial artery diameter was measured at baseline, during postocclusion reactive hyperemia (flow-mediated, endothelium-dependent dilation [FMD]), and after 400 micrograms glyceryl trinitrate (GTN) sublingually (endothelium-independent vasodilation). Vasodilation was expressed as the percentage change relative to the baseline diameter. Baseline flow and blood pressure were similar for IDDM patients and C. Baseline vessel diameter was slightly larger in IDDM patients (3.10 +/- 0.52 mm) compared with C (2.89 +/- 0.55 mm, P = 5.0). FMD in IDDM patients was decreased (12.0 +/- 9.1% versus 15.7 +/- 9.5% in C, P = .046), as was GTN-induced vasodilation (14.9 +/- 8.2% versus 18.3 +/- 8.5% in C, P = .045). After correction for the difference in baseline diameter, FMD and GTN-induced dilation were not different between the groups. GTN-induced vasodilation decreased slightly with increasing diabetes duration. There was no relation between the vasodilatory responses and HbA1c. In normoalbuminuric IDDM patients, endothelium-dependent as well as endothelium-independent vasodilation are normal when the difference in baseline diameter is taken into account.     

Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes

OBJECTIVE: To evaluate the relative value of plasma glucose (PG) at different time points in assessing glucose control of type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Glycemic profiles, i.e., PG at prebreakfast (8:00 A.M.), prelunch (11:00 A.M.), postlunch (2:00 P.M.), and extended postlunch (5:00 P.M.) times over the same day, were obtained in 66 type 2 diabetic patients on an ambulatory basis. The different time points of PG were compared with a measurement of HbA1c made in a reference laboratory. RESULTS: Extended postlunch PG was lower than prebreakfast PG (104 +/- 21 vs. 133 +/- 35 mg/dl, P < 0.02) in patients demonstrating good diabetic control (HbA1c < or = 7.0%), was not different from prebreakfast PG (149 +/- 47 vs. 166 +/- 26 mg/dl, NS) in patients demonstrating fair diabetic control (7.0% < HbA1c < or = 8.5%), and was higher than prebreakfast PG (221 +/- 62 vs. 199 +/- 49 mg/dl, P < or = 0.01) in those demonstrating poor diabetic control (HbA1c < or = 8.5%). Prebreakfast, prelunch, postlunch, and extended postlunch PG values were all significantly correlated with HbA1c. Multiple linear regression analysis demonstrated that postlunch PG and extended postlunch PG correlated significantly and independently with HbA1c, but that prebreakfast PG and prelunch PG did not. Moreover, postlunch PG and extended postlunch PG demonstrated better sensitivity, specificity, and positive predictive value in predicting poor glycemic control than did prebreakfast PG or prelunch PG. CONCLUSIONS: In type 2 diabetes, postlunch PG and extended postlunch PG are better predictors of glycemic control than fasting plasma glucose (FPG). We therefore suggest that they be more widely used to supplement, or substitute for, FPG in evaluating the metabolic control of type 2 diabetic patients.     

Growth hormone-insulin-like growth factor-I axis in adult insulin-dependent diabetic patients: evidence for central hypersensitivity to growth hormone-releasing hormone and peripheral resistance to growth hormone

The aim of this study was to assess the GH-IGFI axis, GH receptor availability, as reflected by the levels of GH-BP, and the amount of GH-dependent IGFBP-3 in adult IDDM patients with different degrees of metabolic control. Thus, 10 adult well-controlled IDDMs (HbA1 7.8 +/- 0.4%), 10 adult non-ketotic poorly controlled IDDMs (HbA1 13.3 +/- 7%) and 14 sex- and age-matched healthy controls were subjected to two intravenous GH-RH stimulation tests with 0.1 and 1.0 microg/kg body weight respectively, and a plasma IGF-1 generation test induced by the administration of hGH. Poorly controlled IDDM patients exhibited an exaggerated GH response to 1.0 microg/kg of GH-RH when compared to healthy control subjects. Low fasting plasma IGF-1 levels and a blunted IGF-1 response to exogenously administered hGH were also found in poorly controlled IDDMs when compared to the healthy control group. GH-BP levels were significantly lower in IDDMs than in normal controls, and correlated positively with the IGF-1 generation capacity after hGH. Serum IGFBP-3 levels measured by RIA were similar in IDDM and control groups. Good glycemic control for 5.7 +/- 0.9 months did not correct the above mentioned abnormalities of the GH-IGF-1 axis. Our findings suggest that IDDM is associated with a diminished availability of GH receptors and synthesis of IGF-1. GH might then increase as a compensatory mechanism, further down-regulating liver GH receptors, and thus perpetuating the initial abnormality.     

Glycosylated hemoglobin and fetal growth in normal, gestational and insulin dependent diabetes mellitus pregnancies

Aims of the study were: evaluation of HbA1c levels in the peripheral blood of pregnant women with insulin dependent diabetes, gestational diabetes, glucose intolerance, and healthy pregnant controls; implications of HbA1c concentration on detection and the control of women with impaired carbohydrate metabolism in pregnancy; comparison of HbA1c levels with appearance of miscarriages, and premature deliveries; comparison of weight gain during pregnancy to HbA1c levels; comparison of difference from ideal body weight with HbA1c in diabetic pregnant women; comparison of neonatal birth weight and HbA1c levels. 290 pregnant women were enrolled to the study. The highest value of HbA1c was in the group IDDM pregnant women (7.7% +/- 1.8%), and the lowest value of HbA1c was in the control group (4.1% +/- 0.5%). Statistically significant coefficients were found between HbA1c and weight gain during pregnancy, between weight deviation from ideal body weight and HbA1c (r = 0.54 and r = 0.48 respectively); and between newborns weight and HbA1c (r = 0.51). Well regulated glycemia and intensive pregnancy follow-up of diabetic women reduces stillbirths, neonatal complications and neonatal macrosomia incidence.     

The JEVIN trial: a population-based survey on the quality of diabetes care in Germany: 1994/1995 compared to 1989/1990

Since 1990 in most Eastern European countries health care systems have been decentralized or are undergoing the processes of decentralization. Increasingly, diabetic patients are no longer treated by diabetologists but by non-specialized physicians. During the same period structured treatment and teaching programmes have been introduced and health care is increasingly influenced by the St. Vincent declaration. To show the effect of these changes on the quality of diabetes care 90% (n = 244) of all insulin-treated diabetic patients aged 16 to 60 years and living in the city of Jena (100247 inhabitants) were studied in 1994/1995. The results were compared with the baseline examination of 1989/1990 (n = 190). HbA1c (HbA1c/mean normal) in IDDM patients under specialized care was similar in 1994/1995 (1.54 +/- 0.27, n = 47) to 1989/1990 (1.52 +/- 0.31, n = 131, p = 0.0018), but higher under non-specialized care (1.71 +/- 0.38, n = 80, p = 0.0087). In the total group of NIDDM patients there was no significant change in HbA1c (1994/1995: 1.75 +/- 0.4, n = 117, vs 1989/1990: 1.78 +/- 0.4, n = 59, p = 0.67), but with a tendency to higher HbA1c under non-specialized (1.81 +/- 0.4, n = 79) compared to specialized care (1.66 +/- 0.39, n = 38, p = 0.06). Incidence of severe hypoglycaemia (IDDM 0.13; NIDDM 0.04), ketoacidosis (0.02; 0.01) and the prevalence of nephropathy (21%; 35%) and neuropathy (24%; 38%) remained unchanged in comparison to 1989/1990, whereas there was an increase in the prevalence of diabetic retinopathy. Specialized care is mandatory for patients with IDDM.     

Use of the short-acting insulin analogue lispro in intensive treatment of type 1 diabetes mellitus: importance of appropriate replacement of basal insulin and time-interval injection-meal

To establish whether lispro may be a suitable short-acting insulin preparation for meals in intensive treatment of Type 1 diabetes mellitus (DM) in patients already in chronic good glycaemic control with conventional insulins, 69 patients on intensive therapy (4 daily s.c. insulin injections, soluble at each meal, NPH at bedtime, HbA1c <7.5%) were studied with an open, cross-over design for two periods of 3 months each (lispro or soluble). The % HbA1c and frequency of hypoglycaemia were assessed under four different conditions (Groups I-IV). Lispro was always injected at mealtime, soluble 10-40 min prior to meals (with the exception of Group IV). Bedtime NPH was continued with both treatments. When lispro replaced soluble with no increase in number of daily NPH injections (Group I, n = 15), HbA1c was no different (p = NS), but frequency of hypoglycaemia was greater (p < 0.05). When NPH was given 3-4 times daily, lispro (Group II, n = 18), but not soluble (Group III, n = 12) decreased HbA1c by 0.35 +/- 0.25% with no increase in hypoglycaemia. When soluble was injected at mealtimes, HbA1c increased by 0.18 +/- 0.15% and hypoglycaemia was more frequent than when soluble was injected 10-40 min prior to meals (Group IV, n = 24) (p < 0.05). It is concluded that in intensive management of Type 1 DM, lispro is superior to soluble in terms of reduction of % HbA1c and frequency of hypoglycaemia, especially for those patients who do not use a time interval between insulin injection and meal. However, these goals cannot be achieved without optimization of basal insulin.     

Factors associated with glycemic control. A cross-sectional nationwide study in 2,579 French children with type 1 diabetes. The French Pediatric Diabetes Group

OBJECTIVE: To determine on a large scale the multiple medical and nonmedical factors that influence glycemic control in the general population of children with diabetes, we performed a nationwide French cross-sectional study. RESEARCH DESIGN AND METHODS: We enrolled 2,579 patients aged 1-19 years with type 1 diabetes of > 1 year's duration. The study was center based: 270 centers were identified, 206 agreed to participate, and 147 included at least 90% of their patients. Questionnaires were completed by physicians interviewing patients and family, and HbA1c measurements were centralized. To identify explanatory variables for HbA1c level and frequency of severe hypoglycemia, we performed multiple regression analysis using all the quantitative variables collected and stepwise logistic regression for the qualitative variables. RESULTS: Mean HbA1c value for the whole population was 8.97 +/- 1.98% (normal 4.7 +/- 0.7% [SD]). Only 19 children (0.7%) had ketoacidosis during the 6 months before the study, whereas 593 severe hypoglycemia events occurred in 338 children (13.8%). Control was better in university-affiliated hospitals and centers following > 50 patients, reflecting the importance of access to experienced diabetologists. Children had a mean of 2.3 injections, allegedly performed 2.8 glucose measurements per day, and were seen an average of 4.6 times per year at the center. In the multiple regression analysis, 94% of the variance of HbA1c was explained by our pool of selected variables, with the highest regression coefficient between HbA1c and age (Rc = 0.43, P < 0.0001), then with daily insulin dosage per kilogram (Rc = 0.28, P < 0.0001), mother's age (Rc = 0.26, P < 0.0001), frequency of glucose measurements (Rc = 0.21, P < 0.0001), and diabetes duration (Rc = 0.14, P < 0.0001). Logistic regression identified quality of family support and dietary compliance, two related qualitative and possibly subjective variables, as additional explanatory determinants of HbA1c. The frequency of severe hypoglycemia was 45 per 100 patient-years and correlated with diabetes duration, but not with HbA1c levels or other variables. CONCLUSIONS: Although overall results remain unsatisfactory, 33% of studied French children with type 1 diabetes had HbA1c < 8%, the value obtained in Diabetes Control and Complications Trial adolescents treated intensively. Diabetes management in specialized centers should be encouraged.     

Low prevalence of microalbuminuria in young Italian insulin-dependent diabetic patients with short duration of disease: a population-based study. Piedmont Study Group for Diabetes Epidemiology

Objectives of this study were to determine the prevalence of microalbuminuria and the level of glycaemic control obtained in a young Italian population-based cohort of subjects with short duration of insulin-dependent diabetes mellitus (IDDM). Out of 298 subjects with onset of IDDM in the period 1984-88, 211 were examined (71%) in 1991-92 (duration of disease 3-9 years). Microalbuminuria was defined as albumin excretion rate (AER) 20-200 micrograms min-1 in an overnight urine collection or alb/creat > 2.5 mg mmol-1 in men and > 4.5 mg mmol-1 in women in one first morning urine sample. Twelve subjects had AER 20-200 micrograms min-1 and 4 had elevated alb/creat ratio. Prevalence of microalbuminuria was 7% (95% Cl 4.0-11.1) in subjects with duration of IDDM 3-9 years and 4% (0.3-7.7) in subjects with duration 3-5 years. Only 1 microalbuminuric subject was found out of 52 aged < or = 14 years. Duration of IDDM was significantly higher (6.9 +/- 1.9 years vs 5.7 +/- 1.6, p = 0.007) and HDL-cholesterol lower (1.22 +/- 0.21 mM vs 1.42 +/- 0.34, p = 0.025) in micro- than in normoalbuminuric subjects, even after adjustment for age, systolic and diastolic blood pressure, BMI, and HbA1c. In almost 50% of the cohort, HbA1c levels were over 9%, whereas only in 10.9% HbA1c levels were lower than 6.6% (mean +3 SD). In conclusion, this Italian population-based study showed low prevalence of microalbuminuria in young subjects with short duration of IDDM, even if the glycaemic control obtained was far from ideal.     

Gastric myoelectrical activity in patients with diabetes. Role of glucose control and autonomic nerve function

OBJECTIVE: Gastric myoelectrical activity was studied in diabetic patients using electrogastrography (EGG) to elucidate the relationship between glucose control, diabetic autonomic neuropathy (AN), and gastrointestinal motility. RESEARCH DESIGN AND METHODS: Cutaneous EGG was recorded during 1 h of fasting and 1 h after the ingestion of a standard meal in 57 diabetic patients and 10 healthy subjects. EGG was measured in 12 diabetic patients after glycemic control for 4 weeks. Diabetic patients were also studied with respect to the presence of gastrointestinal symptoms and AN. RESULTS: The percentage of dominant electrical frequency (DF) in normal range (the percentage ratio between the power at 2.4-3.6 cycles/min [cpm] and at 1-10 cpm) was significantly lower in patients with AN than in either the control subjects or the patients without AN (P < 0.01). The dominant frequency instability coefficient (DFIC) was significantly higher in patients with and without AN than in the control subjects (P < 0.01). The postprandial-to-fasting power ratio (PR) was the lowest in patients with AN (P < 0.01). Multiple regression analysis revealed that HbA1c levels were independently associated with the DFIC (R2 = 0.099, P = 0.0170) and that AN and HbA1c levels were independently associated with the PR (R2 = 0.378, P < 0.0001) in diabetic patients. The percentage of normal DF increased and the DFIC decreased significantly after glycemic control in 12 diabetic patients (P = 0.0409; P = 0.0096, respectively). CONCLUSIONS: There appears to be an association between improvement in gastric myoelectrical activity and autonomic nerve function. Abnormalities of gastric myoelectrical activity may be partly ameliorated via the improvement of autonomic nerve function, which accompanies glycemic control.     

Sonographic patterns by transcranial Doppler in acute cerebral infarction

Microcirculatory changes occur early in insulin-dependent diabetes mellitus (IDDM) and are believed to be an early feature of late diabetic complications, leading to reduced oxygen pressure and hypoxia in the skin and other tissues. Whether muscle oxygen supply is also altered is unknown. Therefore, the authors analyzed polarographic measurements of muscle oxygen tension in 44 healthy type I diabetic patients (mean age 28 years; mean diabetes duration 7 years) and in 57 healthy controls, matched for age, sex, and body mass index, and the corresponding influencing factors. Two measurements were taken at rest 60 minutes apart in the anterior tibial muscle. Muscle oxygen tensions did not differ between IDDM patients and controls (23.0 +/- 8.6 vs 25.3 +/- 9.0 mmHg) and were reproducible on repeated measurements (25.3 +/- 9.7 vs 25.5 +/- 7.4 mmHg). Coefficients of variation were 13.5 +/- 10.8% in IDDM patients and 13.1 +/- 9.3% in controls. Compared with controls, in IDDM patients hemoglobin A1c (HbA1c) and blood glucose concentrations were elevated, and arterial oxygen pressure was significantly lower. Muscle oxygen tensions were positively correlated with blood glucose concentrations in IDDM patients (Rho=0.48, P=0.002) but not with HbA1c or with insulin concentrations. The authors conclude that the polarographic measurement of muscle oxygen tension is a reliable method with good reproducibility. Hypoxia in the anterior tibial muscle of type I diabetic patients can be excluded. In IDDM patients the level of muscle oxygen tension is correlated with the level of blood glucose concentration.     

Enhanced renal vitamin-K-dependent gamma-glutamyl carboxylase activity in experimental rat urolithiasis

OBJECTIVE: To investigate the role of glycemic control and blood pressure in the development and progression of nephropathy and to suggest goals for glycemic control and blood pressure for the prevention of nephropathy in elderly Japanese NIDDM patients. RESEARCH DESIGN AND METHODS: A total of 123 age- and diabetes duration-matched elderly Japanese NIDDM patients (aged 60-75 years; 74 normoalbuminuric and 49 microalbuminuric) were retrospectively studied for 6 years. RESULTS: The group that developed microalbuminuria from normoalbuminuria (group NM: n = 24) showed a higher 6-year mean HbA1c than the group that remained normoalbuminuric (group NN: n = 50; 9.0 +/- 0.8 vs. 8.1 +/- 0.8%, P < 0.01) in spite of no significant difference in 6-year mean blood pressure (MBP). On the other hand, the group that progressed from microalbuminuria to overt proteinuria (group MP: n = 26) showed a higher 6-year MBP than the group that remained microalbuminuric (group MM: n = 23; 106 +/- 5 vs. 95 +/- 6 mmHg, P < 0.01) in spite of no significant difference in 6-year mean HbA1c. The cutoff level of HbA1c separating group NN from group NM was 8.5% (normal range < or = 6.5%), and that of MBP separating group MM from group MP was 100 mmHg. CONCLUSIONS: Glycemic control is a more potent factor than blood pressure level on the development of microalbuminuria. However, as far as the progression of microalbuminuria to overt proteinuria is concerned, hypertension is the most crucial factor in elderly NIDDM patients. Suggested goals for glycemic control and blood pressure level for the prevention of nephropathy in elderly Japanese patients are an HbA1c of < or = 8.5% (equivalent to 7.8% in the current measurement of stable HbA1c; normal range < or = 5.8%) and an MBP of < or = 100 mmHg.     

Familial and perinatal risk factors for micro- and macroalbuminuria in young IDDM patients

It has been suggested that hereditary risk for hypertension and cardiovascular disease (CVD) as well as intrauterine growth may be involved in the pathogenesis of diabetic nephropathy. In the present study, we investigated the influence of familial and perinatal risk factors on the occurrence of micro- and macroalbuminuria in young IDDM patients. A cohort of 1,150 young patients with > or =5 years' duration of IDDM was screened for microalbuminuria. Data on family history of hypertension, CVD, IDDM, and NIDDM; perinatal factors such as birth weight, gestational age, and duration of breastfeeding; and maternal education, smoking, hypertension, and proteinuria during pregnancy were collected. We identified 75 patients with an albumin excretion rate > or =15 microg/min in more than two overnight urinary samples and compared them in a nested case-control study with three normoalbuminuric control subjects per patient from the same cohort, matched for diabetes duration. Perinatal factors were analyzed in all patients born at term (+/- 2 weeks), 59 of the 75 patients and 155 of the 225 control subjects. In univariate analysis, hypertension in parents (odds ratio [OR] 4.21), CVD in parents and grandparents (OR 1.26), maternal smoking during pregnancy (OR 3.21), and a low level of maternal education (OR 2.33) were significantly associated with the development of micro- and macroalbuminuria. When adjusted for other familial and perinatal factors, current mean blood pressure, HbA1c, smoking, BMI, sex, age, and postpubertal diabetes duration, using logistic regression analyses, only parental hypertension in all patients and maternal smoking during pregnancy and low level of maternal education in full-term patients were independent risk factors. When patients with poor glycemic control were analyzed separately, familial CVD, poor metabolic control, parental hypertension, maternal smoking during pregnancy, and level of maternal education were independent risk factors, with the adjusted OR markedly increased, compared with the matched subgroup with better HbA1c. In conclusion, familial hypertension and CVD, maternal smoking during pregnancy, and low level of maternal education may independently increase the risk for incipient nephropathy in full-term offspring who later develop IDDM. Current poor glycemic control seemed to increase the effect of these risk factors.     

Mass spectrometric characterization of nicked fragments of the beta-subunit of human chorionic gonadotropin

To test the hypothesis that hypoglycemia unawareness and impaired counterregulation are reversible after meticulous prevention of hypoglycemia in IDDM patients with diabetic autonomic neuropathy (DAN), 21 patients (8 without DAN [DAN-]; 13 with DAN [DAN+]; of the latter, 7 had orthostatic hypotension [DAN+PH+] and 6 did not [DAN+PH-]) and 15 nondiabetic subjects were studied during stepped hypoglycemia (plateau plasma glucose decrements from 5.0 to 2.2 mmol/l) before and 6 months after prevention of hypoglycemia (intensive therapy). After 6 months, frequency of mild hypoglycemia decreased from approximately 20 to approximately 2 episodes/patient-month while HbA1c increased from 6.2 +/- 0.3 to 6.9 +/- 0.2% (P < 0.05). Responses of adrenaline improved more in DAN- patients (from 1.17 +/- 0.12 to 2.4 +/- 0.22 nmol/l) than in DAN+PH- (from 0.75 +/- 0.25 to 1.56 +/- 0.23 nmol/l) and DAN+PH+ patients (from 0.80 +/- 0.24 to 1.15 +/- 0.27 nmol/l, P < 0.05) but remained lower than in nondiabetic subjects (4.9 +/- 0.37 nmol/l, P < 0.05), whereas glycemic thresholds normalized only in DAN-, not DAN+. Autonomic symptoms of hypoglycemia improved but remained lower in DAN- (6.2 +/- 0.6) than in nondiabetic subjects (8.1 +/- 1.1) and lower in DAN+PH+ (4 +/- 0.8) than in DAN+PH- subjects (5.1 +/- 0.8, P < 0.05), whereas neuroglycopenic symptoms normalized (NS). Cognitive function deteriorated less before than after prevention of hypoglycemia (P < 0.05). Thus, intensive therapy with emphasis on preventing hypoglycemia reverses hypoglycemia unawareness in DAN+ patients despite marginal improvement of adrenaline responses, results in low frequency of hypoglycemia despite impaired counterregulation, and maintains HbA1c in the range of intensive therapy. We conclude that DAN, long IDDM duration per se, and antecedent recent hypoglycemia contribute to different extents to impaired adrenaline responses and hypoglycemia unawareness.     

Muscle sympathetic nerve activity is reduced in IDDM before overt autonomic neuropathy

Studies of heart-rate variability have demonstrated that abnormal cardiac parasympathetic activity in individuals with IDDM precedes the development of other signs or symptoms of diabetic autonomic neuropathy. To determine whether IDDM patients have impaired sympathetic activity compared with normal control subjects before the onset of overt neuropathy, we directly recorded MSNA. We also examined the effects of changes in plasma glucose and insulin on sympathetic function in each group. MSNA was recorded by using microneurographic techniques in 10 IDDM patients without clinically evident diabetic complications and 10 control subjects. MSNA was compared during a 15-min fasting baseline period and during insulin infusion (120 mU.m-2.min-1) with 30 min of euglycemia. A cold pressor test was performed at the end of euglycemia. Power spectral analysis of 24-h RR variability was used to assess cardiac autonomic function. IDDM patients had lower MSNA than control subjects at baseline (8 +/- 1 vs. 18 +/- 3 burst/min, P < 0.02). MSNA increased in both groups with insulin infusion (P < 0.01) but remained lower in IDDM patients (20 +/- 3 vs. 28 +/- 3 burst/min, P < 0.01). In the IDDM group, we found no relationships between MSNA and plasma glucose, insulin, or HbA1c concentrations. BP levels did not differ at rest or during insulin. Heart-rate variability and the MSNA response to cold pressor testing in IDDM patients did not differ from those in healthy control subjects. IDDM patients had reduced MSNA at rest and in response to insulin. The lower MSNA is not attributable to differences in plasma glucose or insulin, but, rather, is most likely an early manifestation of diabetic autonomic neuropathy that precedes impaired cardiac parasympathetic control.     

Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus

BACKGROUND: Good glycaemic control in insulin-dependent diabetes mellitus (IDDM) to prevent complications may be difficult to achieve during adolescence, because abnormalities in production of growth hormone or insulin-like growth-factor-I (IGF-I) can lead to lower insulin sensitivity. Recombinant human IGF-I (rhIGF-I) given as an adjunct to insulin therapy in IDDM, might improve glycaemic control in adolescents; we investigated the effects of the addition of IGF-I in a randomised, double-blind, placebo-controlled trial. METHODS: 53 patients with IDDM (26 male, 27 female) with a median age of 16.1 years (range 10.8-20.6) and diabetes of more than 2 years' duration were randomly assigned subcutaneous rhIGF-I (20 or 40 microg/kg daily [n=18, n=18, respectively]) or placebo (n=17), both in addition to multiple-injection insulin therapy for 24 weeks. The primary endpoint, glycated haemoglobin (HbA1c) and routine biochemistry were measured every 4 weeks. Retinal photographs and glomerular-filtration rates were assessed at base line and at the end of the study. Data were analysed by intention to treat. FINDINGS: With a dose of 40 microg/kg rhIGF-I daily, we found significant reductions in HbA1c compared with placebo (p=0.03), without changes in body-mass index, rate of hypoglycaemia, insulin dose, or circulating concentrations of IGF-binding proteins 1 and 3. The greatest median change in HbA1c of -0.6% (range -2.8 to -1.5%) was seen with rhIGF-I 40 microg/kg at week 12, but was not sustained at week 24. The greatest reductions in HbA1c at week 24 were seen among patients with the greatest changes in IGF-I concentrations (r=-0442, p=0.002). Retinal photographs, renal function (glomerular filtration rate and urinary albumin excretion), and routine biochemistry showed no adverse events. INTERPRETATION: Our data confirm that rhIGF-I as an adjunct to insulin therapy can improve HbA1c values in adolescents with IDDM without overt toxic effects, but they raise questions about whether these effects can be sustained in cases of poor compliance or reduced bioefficacy.     

Biomedical and psychiatric risk factors for retinopathy among children with IDDM

OBJECTIVE: Illness duration and glycemic control influence the development of retinopathy in childhood-onset insulin-dependent diabetes mellitus (IDDM). Psychiatric disorders and sociodemographic factors also affect diabetes-related outcomes. However, biomedical and psychosocial factors have not been examined together in modeling the risk of retinopathy. RESEARCH DESIGN AND METHODS: We conducted a single-site prospective longitudinal study of 66 children (aged 8-13 years) newly diagnosed with IDDM. Repeated assessments served to derive psychiatric diagnoses. Poor glycemic control was defined as the upper 15th percentile of all HbA1 values. After a median follow-up of 10 years, severity of retinopathy was determined. It was modeled with a stepwise polychotomous regression procedure using antecedent biomedical and psychosocial variables. RESULTS: Young adults with childhood-onset IDDM were found to be at increased risk of retinopathy the longer they had IDDM, the more persistently they evidenced poor antecedent glycemic control, and the longer they suffered from depressive illness. These three factors operated individually and additively, with duration of IDDM conferring a baseline level of risk. In depressed patients (27%), depression onset antedated the detection of retinopathy generally by 7 years. CONCLUSIONS: Duration of childhood-onset IDDM confers a baseline level of risk of retinopathy irrespective of glycemic control; antecedent clinical depression is also a risk factor. Depression therefore may serve as a marker of vulnerability and help to identify a subgroup of patients at risk for complications. The findings raise the question whether timely treatment of depression could forestall diabetic retinopathy.