Growth hormone secretion in diabetic retinopathy

Summary The plasma HGH response to insulin-induced hypoglycemia (0.2 U/kg) and the 24-h plasma HGH pattern during a normal day have been studied in 14 non obese long-term insulin-dependent diabetics with proliferative retinopathy, mean age 39 ± 2 (ranging between 24 and 50 years). Plasma glucose and FFA were also determined. The results were compared with those of 18 normal subjects of similar age and weight. The mean plasma HGH response to insulin in retinopathic diabetics was slightly lower (with no significant differences) than in controls in whom hypoglycemia was induced with a smaller dose of insulin (0.1 U/kg). This pattern of plasma HGH could be related to the delayed plasma glucose fall observed in retinopathic diabetics in comparison to normal subjects, even if the HGH peak after insulin in both groups (18.61 ± 4.32 ng/ml in retinopathic diabetics, 27.43 ± 4.19 in controls) did not seem to be correlated to the degree of hypoglycemia, but rather to the age of the subjects. Plasma HGH pattern, studied with blood samples taken every three hrs during a normal day, did not reveal differences between the diabetics and controls. Plasma glucose, however, was higher in retinopathic diabetics than in controls in spite of the insulin treatment. These results show that in diabetic patients with retinopathy, increased HGH secretion does not occur in conditions of ordinary life or after insulin-induced hypoglycemia, although the HGH plasma levels observed in retinopathic diabetics could be considered too high in relation to the elevated blood glucose levels. Traduzione a cura degli AA.     

Growth hormone release in unstable diabetes: Tests with saline,arginine, glucagon,and epinephrine

Summary Changes in plasma growth hormone (HGH) concentrations during tests with arginine, glucagon, epinephrine and saline were compared in 8 unstable and 4 stable diabetics, and 5 normal subjects. These same subjects had previously also been tested with insulin-induced hypoglycemia and their blood glucose variability had been quantified during near-normal (ambulatory-fed) living conditions. Compared with saline infusion, arginine induced higher HGH increases but glucagon and epinephrine did not. Compared to preinfusion levels, epinephrine decreased HGH concentrations. Patterns of mean HGH increase and decrease after arginine were similar in the 3 groups of subjects. Only during saline infusion did unstable diabetics have higher peak levels than did stable diabetics and normal subjects. The higher or similar increases of HGH in unstable diabetics always occurred at higher concentrations of blood glucose and frequently, but not invariably, at higher concentrations of serum free fatty acids and ketone bodies than in stable diabetics and in normals. HGH release is abnormal in unstable diabetics in that hyperglycemia does not inhibit the release of HGH. The abnormality is associated with impaired modulation of blood glucose and other variables through inability to secrete endogenous insulin. Traduzione a cura degli AA.     

Effect of aging on growth hormone,ACTH and cortisol response to insulin-induced hypoglycemia in type I diabetes

Summary The influence of age on plasma growth hormone (GH) response to i.v. insulin (0.2 U/kg body weight) was evaluated in clinically stable type I (insulin-dependent) diabetics divided into four age groups (range 18–80 years). ACTH and cortisol were also assayed in two groups of diabetics under and over 50 years of age. A significant reduction with aging in GH response to insulin was observed. On the contrary, the glucose fall was similar in all the groups. ACTH and cortisol responses to insulin were slightly decreased in the older diabetics. Since insulin-induced hypoglycemia was similar in all the age groups, the progressive decline with aging in the GH response to insulin may be attributed to age-related changes of the pituitary gland. The data on ACTH and cortisol are less striking. Our data, as a whole, confirm that growth hormone response to insulin-induced glucose fall is not critical in acute glucose counterregulation in insulin-dependent diabetics. In fact, in spite of a 4-fold difference in GH levels, there was no difference in the 2-h glycemic course after 0.2 U/kg of i.v. insulin between young and aged patients. When a group of 26 type I diabetics with proliferative retinopathy was compared with a group of age-matched type I diabetics without retinopathy and with 30 age-matched normal subjects (injected i.v. with 0.1 U/kg body weight of insulin), no difference was found in GH response to insulin, indicating that GH hypersecretion is not a characteristic finding of diabetic retinopathy. This study was supported by grant N. 83.02749.56 fromConsiglio Nazionale delle Ricerche.     

Growth Hormone Response to Hyperinsulinaemia in Insulin-dependent Diabetics Comparison of Patients With and Without Retinopathy

Growth hormone levels were measured in glucose clamp studies on 13 insulin-dependent diabetic patients with retinopathy and 9 age, sex, and weight matched patients without retinopathy. Four non-diabetic subjects were used as controls. The glucose was kept constant at 12 ± 0.85 mmol/I (mean±S.D.) in the diabetic groups, and at 6 mmol/I in the non-diabetic controls. Insulin was infused at sequential rates of 0.3, 1.0, and 10 mU/kg/min. Basal levels of growth hormone were not significantly different in those with and without retinopathy (5.7 ± 4.9, 9.4± 10.6 mU/I p = 0.21). Growth hormone levels were compared in each group during a 60 minute steady state period for each insulin infusion rate. At all 3 infusion rates, the diabetics with retinopathy produced a rise in growth hormone, while the non-diabetics did not (1.24 ± 0.6 mU/I). The patients with retinopathy produced more growth hormone than those without at each infusion rate (12.2 ± 11.5 vs. 2.8 ± 5.1, p = 0.03; 10.6±11.1 vs. 1.6±1.7, p = 0.02; 19.7±20.6 vs. 4.2 ± 4.8, p = 0.03). These data confirm that insulin alone can stimulate growth hormone secretion in insulin-dependent diabetics with retinopathy. Evidence is provided indicating that patients with retinopathy produce more growth hormone than those without.     

Glycemic control with an artificial pancreas improves insulin responses to both oral and I.V. Glucose in nonobese noninsulin-dependent diabetic subjects

Summary Insulin secretory responses to both oral and intravenous glucose were investigated in 12 nonobese noninsulin-dependent diabetic subjects before and after strict metabolic control of blood glucose levels without weight loss. Glycemic control was achieved by applying an artificial pancreas to all diabetics for 2 or 3 days, which led to restoration of normal fasting blood glucose levels and to significant reduction of fasting plasma insulin (p<0.01) and C-peptide (p<0.05) levels. Initially, the insulin response to oral glucose was weak and delayed, but increased significantly after treatment (p<0.01), although none of the diabetic subjects achieved completely normal glucose tolerance. The i.v. glucose tolerance test (0.33 g/kg) revealed that all diabetics lacked acute insulin response in the basal state with low glucose disappearance rates (0.37±0.07 %/min). After 48h of normoglycemia, these figures did not change significantly, although the insulinogenic index (insulin area/glucose area) was significantly increased (p<0.05). A marked increase in both phases of insulin secretion was evident when a larger intravenous glucose pulse (0.66 g/kg) was used in some diabetics in order to raise the blood glucose concentrations of the post-treatment test to those of the pre-treatment test. In absolute terms, the insulin responses of the post-treatment tests were not significantly different from those of sex, age- and weightmatched control subjects, but were signficantly lower if related to the corresponding plasma glucose responses (insulinogenic index lower than that of controls). These studies in nonobese noninsulin-dependent diabetic subjects indicate that glycemic control with an artificial pancreas improves insulin response to glucose, suggesting that chronic hyperglycemia may stress the impaired B-cell secretory capacity of diabetes.     

Beta-blockers in hypertensive non-insulin-dependent diabetics: Comparison between penbutolol and propranolol on metabolic control and response to insulin-induced hypoglycemia

Summary In a single blind randomized study the effects of a 4-week administration of propranolol (160 mg/day) and penbutolol (40 mg/day) on metabolic control and insulin-induced hypoglycemia were tested in 8 non-insulin-dependent diabetics with diastolic blood pressure between 95 and 110 mmHg. The recovery from hypoglycemia was not delayed by either drug; hypoglycemic nadir and Conard’sK did not change significantly. Symptoms of hypoglycemia were inhibited to a lesser extent and pulse rate decrease was lower after penbutololvs baseline (65±2.4vs 77±2.4 beats/min, p<0.01) than after propranololvs baseline (61±1.06vs 77±2.4 beats/min p<0.001). Both drugs produced similar and significant effects on blood pressure both systolic and diastolic. There were no significant effects on fasting plasma glucose concentration, HbA_tc, IRI, urinary C-peptide, triglycerides, total and HDL cholesterol and FFA. IRG decreased after penbutololvs baseline 60 min after insulin injection (170±30.8vs 125±15.4 pmol/l, p<0.05). These results indicate that the use of beta-blockers, in particular penbutolol, for mild to moderate hypertension may be considered the treatment of choice also in non-insulin-dependent diabetics at the therapeutic doses employed.     

Evidence for marked sensitivity to the antilipolytic action of insulin in obese maturity-onset diabetics.

Changes in plasma free fatty acids (FFA) observed during oral glucose tolerance tests in 12 obese maturity-onset diabetic Pima Indians with insulin response to oral glucose averaging only 7 ± 19 μU/ml above fasting were compared to those of 11 obese nondiabetic Pima Indians and 10 obese nondiabetic Caucasions who had mean insulin responses of 252 ± 34 and 73 ± 18 μU/ml, respectively. Fasting free fatty acid levels in the diabetics were higher, but they showed decreases similar to controls (278 ± 55 versus 284 ± 32 for nondiabetic Pima controls and 262 ± 43 μeq/liter below fasting for nondiabetic Caucasions). Plasma glycerol levels showed decreases parallel to those of free fatty acids, indicating that the FFA changes in the diabetics were attributable to inhibition of lipolysis rather than to increased removal. During intravenous glucose tolerance tests (IVGTT) in these diabetics, insulin levels decreased initially and there was no decline in FFA. In a second group of less severe diabetics (N = 6), whose increments in insulin during intravenous glucose tolerance tests averaged 15 ± 4.1 μU/ml above fasting, FFA decreases were again comparable to Pima and Caucasion nondiabetics (214 ± 53, 234 ± 37, and 183 ± 51 μeq/liter below fasting, respectively). These findings demonstrate marked sensitivity to the antilipolytic effects of insulin in individuals considered to be resistant to its glucose-lowering action.     

Mechanism of the blunted glucagon response to insulin-induced hypoglycemia in diabetics

It has been widely reported that dysfunctions of pancreatic A-cell occur in diabetics. Since these pancreatic A-cell dysfunctions are not normalized by conventional insulin injection treatment, they were thought to be a primary defect of diabetes mellitus. Recently it was found that paradoxic glucagon secretion to oral glucose and excessive glucagon response to i.v. arginine could be perfectly normalized if strict blood glucose regulations were achieved with appropriate insulin treatment. However, there has been no report on the perfect normalization of glucagon secretion in response to insulin-induced hypoglycemia in diabetics. In this report, to elucidate the precise significance of A-cell function in hypoglycemia in diabetics, the effect of long-term strict glycemic regulations and the importance of intact autonomic nerve function on hypoglycemia-induced glucagon secretion were studied. In experiments on hypoglycemia-induced glucagon secretion in diabetics, 0.2 to 0.3 U/kg of regular insulin injection were usually employed to overcome the hyperglycemia and insulin resistance. However, hyperinsulinemia has been demonstrated to suppress A-cell function in experiments using the euglycemic clamp technique. Therefore, the effect of plasma insulin concentrations after insulin injections was first studied in 7 healthy volunteers by injecting insulin at doses of 0.1 U/kg and 0.3 U/kg. In this experiment with 0.3 U/kg of insulin, the rate of fall in glycemia and the nadir of blood glucose were made similar to that with 0.1 U/kg of insulin by using glucose clamp technique with artificial endocrine pancreas. The plasma glucagon response after 0.3 U/kg of insulin was significantly suppressed as compared to that after 0.1 U/kg of insulin. From these experiments, it was concluded that not only hypoglycemic stimuli but also plasma insulin concentrations are important factors for demonstrating significant glucagon secretion in response to insulin-induced hypoglycemia. Second, the effects of strict glycemic control and autonomic nerve function on hypoglycemia-induced glucagon secretion were studied. Regular insulin at a dose of 0.1 U/kg was injected in an i.v. bolus form into 21 insulin-dependent (IDDM) and 22 noninsulin-dependent (NIDDM) diabetics before and one to three months after strict glycemic control with multiple insulin injection therapy or continuous subcutaneous insulin infusion therapy. To reduce fasting blood glucose level and to obtain the same hypoglycemic stimuli, overnight insulin infusion at a basal dose was undertaken in IDDM who showed hyperglycemia before strict glycemic regulations.(ABSTRACT TRUNCATED AT 400 WORDS)     

INSULIN SECRETORY CAPACITY, β-THROMBOGLOBULIN and BLOOD VISCOSITY IN LONG STANDING, NON-INSULIN DEPENDENT DIABETICS WITH and WITHOUT MICROANGIOPATHY

A comparison was made of insulin secretion in response to i.v. glucose between non-insulin dependent diabetics with and without severe microangiopathy. During i.v. glucose tolerance testing those with complications had significantly lower serum insulin concentration (at 40 and 60 min 15.2 ± 2.9 and 11.7 ± 2.5 mll-1 respectively) than those without (26.1 ± 4.7 and 24.3 ± 3.6 mU-1, p <0.01). The differences were also significant when insulin increment above basal was determined. All subjects had raised plasma beta-thromboglobulin concentration (indicating increased tendency to platelet aggregation), but with no significant difference between the two groups. There was also no difference in fasting glucose, kg values, HbAI or blood viscosity. We conclude that non-insulin dependent diabetics with severe microangiopathy have significantly reduced insulin secretory capacity in response to i.v. glucose when compared with those without.     

Severe hypoglycemia in diabetics requiring hospitalization and short-term mortality

We planned a prospective study to observe short-term mortality in diabetic patients with severe hypoglycemia requiring hospitalization. Total 50 patients were enrolled in the study. Diabetic patients presenting to hospital with plasma glucose <70 mg/dl requiring hospitalization for correction were enrolled in study. Patients with underlying malignancy, acute cerebro-vascular event, symptomatic congestive heart failure, and creatinine clearance <10 ml/min/1.73 m² were excluded. All subjects were followed for 3 months from date of admission. Majority of patients were type 2 diabetics (41, 82%) and remaining were type 1 diabetics. Mean age of type 1 diabetic was 31.77 ± 8.9 years and for type 2 diabetic was 65.97 ± 10.5 years. Mean plasma glucose at presentation was 36.62 ± 11.57 mg/dl. Fourteen (28%) patients had previous admission with hypoglycemia. Thirty patients did not have knowledge about hypoglycemia management at home. Seventeen (34%) were on single drug (insulin/SU), 19 (38%) were on two drugs, and 14 (28%) were on three or more drugs. Mean creatinine clearance was 55.83 ± 26.5 ml/min/1.73 m². Mean HbA1C was 8.58 ± 1.94%. Total in-hospital mortality was two (4%), and two more deaths were observed during 3-month follow-up. All four deaths occurred in type 2 diabetics who were illiterate and had no previous history of severe hypoglycemia. Total in-hospital mortality was 2/50 (4%) and 90-day all-cause mortality was 4/50 (8%). All patients who died were type 2 diabetic; hence, all-cause mortality was 4/41 (9.7%) in type 2 diabetes. Our study suggests that severe hypoglycemia, particularly in type 2 diabetes, is associated with very significant all-cause mortality in short term.     

A role for endogenous prostaglandins in defective glucose potentiation of nonglucose insulin secretagogues in diabetics

Noninsulin dependent diabetics have insulin responses to nonglucose secretagogues that are subnormal for their plasma glucose levels. Since endogenous prostaglandins have been implicated in the abnormal insulin responses to glucose in diabetics, the present study was performed to explore whether prostaglandins might also play a role in the defective insulin responses to nonglucose stimuli. We examined the effects of infusions of either prostaglandin E₂ (PGE₂) or sodium salicylate (SS), a PG synthesis inhibitor, on the acute insulin responses (AIR's) to arginine and isoproterenol and on the glucose potentiation of the insulin response to arginine in both normal and diabetic subjects. The AIR to arginine was augmented by SS in diabetics (SS = 61 ± 12 μU/ml, control = 37 ± 5 μU/ml, n = 11, p < .01). SS, however, had no effect on the AIR to arginine in normal subjects (SS = 39 ± 4 μU/ml, control = 34 ± 4 μU/ml, n = 6, p = ns). Similarly, SS augmented the AIR to an isoproterenol pulse in diabetics (SS = 38 ± 9 μU/ml, control = 18 ± 3, n = 9, p < .05) but not in normal subjects (SS = 19 ± 4 μU/ml, control = 21 ± 4 μU/ml, n = 8, p = ns), suggesting a SS-sensitive defect in the insulin response to these nonglucose stimuli in diabetics. Conversely, PGE₂ inhibited the AIR to arginine in diabetics (PGE = 28 ± 5 μU/ml, control = 39 ± 7 μU/ml, n = 7, p < .05), but not in normal subjects (PGE = 74 ± 7 μU/ml, control = 80 ± 14 μU/ml, n = 5, p = ns). The effect of SS on glucose potentiation of the AIR to arginine was studied by measuring the AIR to arginine at two different levels of plasma glucose, one before and one after an insulin infusion, with glucose potentiation defined as the ratio ΔAIR/Δprestimulus glucose. Glucose potentiation was significantly less in diabetics than in normals and SS significantly improved glucose potentiation toward normal values in diabetics but did not change glucose potentiation in normals. These findings suggest that endogenous PG's may play a role in the defective glucose potentiation of the AIR to nonglucose secretagogues in diabetics resulting in impaired insulin responses to these stimuli. This defect is partially reversible by an inhibitor of PG synthesis.     

Arginine vasopressin and oxytocin responses to insulin-induced hypoglycemia in type 1 (insulin-dependent) diabetes

In normal humans, arginine vasopressin and oxytocin are released acutely from the posterior pituitary gland in response to hypoglycemia, and their release may assist counterregulation. The responses of these hormones to insulin-induced hypoglycemia were measured in 16 insulin-dependent diabetic patients with no autonomic neuropathy (8 patients who had been diabetic less than 5 yr and 8 patients who had been diabetic greater than 15 yr) and in 6 normal subjects. The time of the onset of hypoglycemia and the mean blood glucose nadirs were similar in all groups, but the blood glucose recovery was delayed in the diabetic patients. In the normal subjects plasma arginine vasopressin rose from a mean basal value of 0.4 +/- 0.2 (+/- SE) pmol/L to a maximum of 1.3 +/- 0.6 pmol/L, and plasma oxytocin rose from 0.7 +/- 0.1 pmol/L to a maximum of 1.2 +/- 0.2 pmol/L 30 min after the onset of hypoglycemia. The plasma arginine vasopressin and oxytocin concentrations after hypoglycemia were significantly higher in both of the diabetic groups compared with those in the normal group. Arginine vasopressin and oxytocin rose in all control subjects after hypoglycemia. The individual hormonal profiles in the diabetic patients were variable, with an exaggerated rise of oxytocin in some diabetic patients and no rise in others. The arginine vasopressin responses were exaggerated in all of the diabetic patients. There was no correlation between the hormonal responses and the duration of diabetes. The exaggerated plasma arginine vasopressin and oxytocin responses to hypoglycemia in diabetic patients may indicate the failure of a normal inhibitory mechanism which modulates hormonal secretion or a compensatory response to impaired glucose recovery.     

Dose-kinetics of pancreatic glucagon responses to arginine and glucose in subjects with normal and impaired pancreatic B cell function

Summary Pancreatic glucagon responses to different amounts of intravenous arginine and glucose were studied in 10 insulin-dependent diabetics, 14 healthy controls (high insulin responders) and 15 subjects with decreased insulin response to glucose but normal intravenous glucose tolerance (low insulin responders). The dose-kinetics of the glucagon response was studied by using four different arginine doses. The suppressive effect of glucose was evaluated by infusing three glucose doses during a submaximal stimulation with arginine. The diabetics were tested first when under fair metabolic control and then following intensive treatment with insulin to produce near-normalisation of blood glucose. Finally, five subjects underwent insulin-induced hypoglycaemia. The changes in plasma glucagon and blood -amino-nitrogen in response to the four arginine doses were significantly correlated in all groups but the slope of the dose response curve was steeper in the poorly controlled-diabetics than in the non-diabetics. These diabetics displayed higher fasting plasma glucagon values than healthy controls (high insulin responders) (224±4 versus 151±22 pg/ml, p<0.01), higher plasma glucagon responses to arginine and an absence of inhibition by glucose of the arginine-stimulated glucagon release. In strictly controlled diabetic patients, fasting plasma glucagon levels (176±16 pg/ml) were not significantly different from healthy controls, the glucagon response to arginine returned to the normal range, A cell suppressibility by glucose was restored and A cell stimulation by hypoglycaemia reappeared. In the low insulin responders, fasting plasma glucagon was not different from that of high responders (107±12 pg/ml), the slope of the dose response curve to arginine was similar in both groups and the A cells were inhibited by glucose to a similar extent. These results support the concept that islet A cell dysfunction in diabetes is not a primary phenomenon.     

Does mitochondrial genome mutation in subjects with maternally inherited diabetes and deafness decrease severity of diabetic retinopathy?

Two types of retinopathy, diabetic and pigmentary, may be seen in subjects with maternal inheritance diabetes and deafness. The potential for interactions between the two retinopathies has not been explored. The mitochondrial mutation may affect development of diabetic retinopathy in subjects with MIDD by altering normal pathways of glucose metabolism. We identified five unrelated MIDD kindreds with 61 living maternal line family members. Twenty-three of the family members, 12 with diabetes mellitus and 11 without volunteered to be studied. Subjects were graded for severity of diabetic retinopathy and presence or absence of pigmentary retinopathy after slit lamp biomicroscopy, retinal photography of seven standard fields and fluorescein angiography. Blood was taken, in the fasted state, from MIDD subjects (duration of diabetes 17.0 ± 6.9 yr) and non-diabetic subjects with the mutation, for assay of sorbitol and glucose and values compared with diabetic and non-diabetic control subjects without the mutation. Diabetic retinopathy was absent in 9/12 subjects (75 %), with 3 having mild non-proliferative retinopathy. No one had cataract. Red blood cell sorbitol levels, adjusted for ambient blood glucose, were significantly lower in MIDD subjects compared with diabetic subjects (1.16 ± 0.5 cf. 2.03 ± 1.1, × 10⁻³ g mmol⁻¹, p = 0.04). Pigmentary retinopathy was present in 15 of 23 subjects, of whom 13 had some abnormality of glucose tolerance. Abnormal glucose tolerance was strongly associated with the development of pigmentary retinopathy (odds ratio 19.5, p = 0.008). In conclusion, there appears to be a decreased prevalence of diabetic retinopathy and cataract in MIDD, which we propose is due to reduced glucose metabolism by the polyol pathway. Abnormal glucose tolerance increases the clinical expression of pigmentary retinopathy in subjects with a mitochondrial genome mutation. A greater understanding of the metabolic effects of mitochondrial DNA mutations has the potential to give insight into the mechanisms of diabetic retinopathy and other complications of diabetes mellitus. © 1998 John Wiley & Sons, Ltd.     

Insulin resistance in diabetic microangiopathies

To investigate whether insulin resistance is associated with diabetic microangiopathies in type 2 diabetes mellitus, insulin sensitivity was measured in 133 type 2 diabetic subjects with or without diabetic retinopathy and/or nephropathy. Insulin sensitivity was measured by steady-state plasma glucose method or euglycemic glucose clamp method. Regarding retinopathy, in the insulin-resistant group, advanced retinopathy (preproliferative and proliferative retinopathy) was more frequently observed compared with the insulin-sensitive group (significance: p<0.02). Similarly, as for nephropathy, the occurrence of continuous proteinuria in the insulin-resistant group was significantly (p<0.01) more frequent compared with the insulin-sensitive group. Insulin sensitivity expressed as glucose utilization and glucose clearance was significantly (p<0.05) lower in diabetic subjects with retinopathy (without nephropathy) compared with subjects without the microangiopathies after adjustment for age, body mass index (BMI), fasting blood glucose (FBS), and diabetic duration. Similarly, insulin sensitivity in subjects with nephropathy (without retinopathy) was significantly (p<0.05) decreased compared with those without microangiopathies. Furthermore, insulin resistance was significantly (p<0.01) severe in the subjects with both retinopathy and nephropathy than in those without the two microangiopathies. Insulin resistance of type 2 diabetes is closely associated with the progression of microangiopathies, and causal relationship between insulin resistance and microangiopathies has remained to be solved.     

Impaired Counter Regulation of Hypoglycemia in a Group of Insulin-dependent Diabetics with Recurrent Episodes of Severe Hypoglycemia

Abstract The counterregulatory response to insulin-induced hypoglycemia was investigated in 22 insulin-dependent diabetics (IDD) with recurrent hypoglycemia and in 6 healthy volunteers. Hypoglycemia was induced by a constant rate infusion of insulin (2.4 U/h) up to four hours. Conventional insulin therapy was changed to an i.v. infusion of regular insulin 24 hours prior to the experiment. The presence of diabetic autonomic neuropathy was evaluated by respiratory sinus arrhythmia and Valsalva maneuver. In healthy subjects, blood glucose was decreased to 2.5 mmol, here reaching steady state level and giving rise to marked glucagon and growth hormone (GH) responses. The majority of IDD (group A) reached a slightly lower steady state glucose level and exhibited similar glucagon and GH responses while the epinephrine response was augmented. Six IDD (group B) showed a continuous decrease in blood glucose to 1.2+0.1 mmol/l at which level the infusion of insulin was discontinued due to neuroglucopenic symptoms. These subjects had no glucagon and epinephrine responses while their GH and cortisol responses were normal. A comparison of the diabetic groups revealed a longer duration of diabetes and a more impaired autonomic nervous function in group B while glycosylated hemoglobin was similar. It is concluded that most IDD have normal hormonal responses (epinephrine, glucagon, GH, cortisol) and normal counterregulartory capacity to hypoglycemia induced by a prolonged infusion of a moderate dose of insulin. Some patients with long-term diabetes and impaired capacity to counteract hypoglycemia exhibit deficient glucagon and epinephrine responses to hypoglycemia.     

Thyrotropin and prolactin responses to thyrotropin-releasing hormone: influence of fasting- and insulin-induced changes in glucose metabolism

It has been reported that prolonged fasting inhibits the response of thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) in normal persons. To explore possible mechanisms behind this reduced TSH responsiveness and also to see whether dietary factors influence prolactin (PRL) responsiveness, six nonobese volunteers were intravenously injected with a small dose of TRH (25 μg) after three different fasting periods: an 8-hour overnight fast, a 56-hour fast supplemented with oral administration of glucose (4 g/kg/56 h yielding 16 kcal/kg/56 h), and a 56-hour fast supplemented with oral administration of an equicaloric amount of an amino acid (AA) mixture (4 g/kg/56 h) containing 17 different amino acids. The dose of TRH raised the PRL level from 14 ± 2 to 58 ± 8 ng/ml after the overnight fast. Similar PRL responses were obtained after the two prolonged fasting periods. The TRH also raised the TSH level from 1.0 ± 0.0 to 5.2 ± 0.8 μU/ml after the overnight fast. Prolonged fasting with glucose supplementation had no significant effect on this TSH responsiveness, nor did it change the basal blood glucose level. In contrast, prolonged fasting with AA supplementation not only reduced TSH responsiveness by 47 ± 7% (P < 0.002), it also lowered the basal blood glucose level from 4.2 ± 0.1 to 3.5 ± 0.2 mmol/L (P < 0.002). In an additional six normal subjects who fasted overnight, 25 μg TRH was injected intravenously on two occasions: after intravenous infusion of insulin, and after intravenous infusion of saline. The insulin induced market hypoglycemia (1.8 ± 0.1 mmol/L) in 30 ± 3 minutes, whereas saline, infused over a similar time period, had no significant influence on the blood glucose level. When PRL responsiveness was measured during the insulin-induced hypoglycemia, it was found to be increased by 56 ± 15% (P < 0.02). The corresponding TSH responsiveness was decreased by 18 ± 6% (P < 0.05). These results imply that an adequate glucose delivery to pituitary thyrotrophs might be a prerequisite for normal TSH responsiveness. They also show that changes in glucose utilization affect lactotrophs and thyrotrophs differently.     

Diabetic retinopathy assessed by fundus photography in Pima Indians with impaired glucose tolerance and NIDDM

In a population-based epidemiological study, 991 Pima Indians with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and 288 without diabetes aged ≥15 years were examined for retinopathy by fundus photography with a 45° fundus camera after mydriasis. The photographs were graded using a modified Airlie-House classification scheme. The associations of several factors with retinopathy were studied by logistic regression. Non-proliferative retinopathy was present in 11.2 % (19/169) subjects at the time of diagnosis of diabetes and in 8.3 % (4/48) in newly diagnosed subjects who had a documented non-diabetic oral glucose tolerance test within 4 years prior to diagnosis of diabetes. The prevalence of retinopathy in subjects with impaired glucose tolerance was 12 % (8/68). Retinopathy at the time of diagnosis of diabetes was significantly associated with lower body mass index and higher systolic blood pressure but not glycaemia. Retinopathy was present in 375 (37.8 %) diabetic subjects and 14 (5.2 %) non-diabetic subjects. Among all subjects with diabetes (duration 0–37 years), stepwise multivariate analysis showed non-proliferative retinopathy to be associated with duration of diabetes, mean blood pressure, fasting plasma glucose, treatment with insulin and albuminuria. Proliferative retinopathy was seen in 34 (2.7 %) of diabetic and none of the non-diabetic subjects, and was associated with 2 h post-load glucose concentrations, as well as albuminuria, insulin treatment, younger age, and diastolic blood pressure. These data confirm the need for fundus examination at the time of diagnosis of diabetes and during long-term follow-up. Albuminuria and blood pressure are potentially modifiable risk factors and the impact of treating these on incidence and progression of diabetic retinopathy need to be assessed. © 1997 by John Wiley & Sons, Ltd.     

初诊2型糖尿病患者微血管病变的患病率及相关危险因素分析

目的明确北京地区初诊2型糖尿病患者微血管病变(外周神经病变,视网膜病变,糖尿病肾病)的患病率,并对其相关危险因素进行分析。方法对402例新诊断的2型糖尿病患者进行眼底荧光造影和尿微量白蛋白、神经传导速度及相关指标测定,计算微血管病变的患病率,并对相关因素行Logistic回归分析。结果(1)初诊糖尿病的患者中糖尿病肾病的患病率为16.1%;糖尿病视网膜病变的患病率为18.7%;糖尿病神经病变的患病率为37.3%。(2)收缩压和糖化血红蛋白为糖尿病视网膜病变的独立危险因素。(3)年龄、收缩压、舒张压、空腹血糖、餐后两小时血糖及糖化血红蛋白为糖尿病外周神经病变的独立危险因素。(4)初诊2型糖尿病女性糖尿病视网膜病变、糖尿病肾病的患病率高于男性。结论北京地区初诊2型糖尿病微血管病变占一定比例,微血管病变的患病率存在性别差异,控制血压、血糖有利于改善糖尿病微血管病变。     

Somatomedin-C (Sm-C). Study in diabetic patients with and without retinopathy

Summary In the present study we evaluated somatomedin-C (Sm-C) plasma levels in diabetic patients, with and without retinopathy. One hundred and thirty four diabetic patients (65 type I and 69 type II) and 90 controls, strictly matched for age and sex, were enrolled in the study. Ophthalmoscopy and fluorescein angiography allowed to distinguish: 49 patients without retinopathy, 45 patients with background retinopathy, and 40 with proliferative retinopathy. Growth hormone (GH) and Sm-C plasma levels were measured using a pool of 20–24 blood samples over 24h. Sm-C levels in type I (0.62±0.11 U/ml) and type II (0.56±0.09 U/ml) patients were significantly decreased (p<0.01) when compared to controls (0.89±0.30 U/ml). The mean daily secretion of GH was significantly (p<0.01) greater in diabetic patients (7.8±2.6 ng/ml) than in controls (4.1±1.5 ng/ml), but no correlation was found between Sm-C and GH (r=0.15; p=n.s.). Our findings did not show any correlation between Sm-C plasma levels and either the existence of retinopathy, regardless of the degree of microvascular damage, or duration of the disease, or degree of metabolic control, as evaluated by HbA_1c.