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Biomedical subjects

C Coscelli

Publications and source records attributed to C Coscelli.

At least 19 recordsLinked to original sources

Importance of premeal injection time in insulin therapy: Humalog Mix25 is convenient for improved post-prandial glycemic control in type 2 diabetic patients with Italian dietary habits.

We investigated the use, in a short period, of Humalog Mix25 (Mix25) in a twice-daily administration regimen compared to a twice-daily injection therapy with Humulin 30/70 (30/70) in diabetic patients with Italian dietary habits. We studied 33 type 2 diabetic patients aged 59.1 +/- 8.1 years, BMI 29.8 +/- 2.7 kg/m2, duration of diabetes and insulin therapy of 14.4 +/- 9.8 and 4.2 +/- 4.6 years, respectively. After a 4-day lead-in period of twice-daily human insulin 30/70 treatment, patients were randomized to one of two treatment sequences: (1) a twice-daily regimen with Mix25 just 5 minutes before the morning and evening meals for 12 days, followed by a twice-daily therapy with human insulin 30/70 given 30 minutes before the morning and evening meals for an additional 12 days; or (2) the alternate sequence. Each patient underwent a mixed meal test: Humulin 30/70 was administered 30 minutes before the meal, while Mix25 was given 5 minutes before. The 2-hour post-prandial glucose concentration after breakfast was significantly lower during treatment with Mix25 than with Humulin 30/70 (157 +/- 43.2 vs. 180 +/- 43.2 mg/dl, p<0.05). The glycemic excursion after dinner on Mix25 treatment was significantly lower than with Humulin 30/70 (12.2 +/- 48.01 vs. 35.5 +/- 36.92 mg/dl, p<0.05). AUCglucose after Mix25 was lower than after Humulin 30/70. Glycemia after test meal was significantly lower with Mix25 than with Humulin 30/70. Insulin and free insulin concentrations after the test meal were significantly higher with Mix25 in comparison to Humulin 30/70. AUC serum insulin and free insulin curves after Mix25 were significantly higher than after Humulin 30/70 (p=0.028 and p=0.005, respectively). Twice-daily injections of Humalog Mix25, compared to human insulin 30/70 in type 2 diabetic patients with Italian dietary habits, provide improved and lasting post-prandial glycemic control, with the great convenience of the injection just before the meal.

Biphasic Insulins↗

Cigarette smoking: a risk factor for erectile dysfunction in diabetics.

OBJECTIVES: Diabetes is one of the systemic disorders most frequently associated with erectile dysfunction (ED). An extensive literature documents well the relationship between ED and several factors related to diabetic pathology, but the role of risk factors mainly related to life-style, e.g. cigarette smoking, is still not defined. METHODS: Eligible for the study were men aged 20-70 years with a diagnosis of insulin-dependent (type 1---IDDM) or non-insulin-dependent (type 2--NIDDM) diabetes who were observed on randomly selected days in 178 diabetes centers in Italy. ED was defined as a failure to achieve and maintain an erection sufficient for satisfactory sexual performance. RESULTS: The study population consisted of 9,670 diabetic men. Of these 2,962 (30%) were never smokers, 2,877 (30%) current smokers and 3,831 (40%) ex-smokers. After taking into account the effect of age, the odds ratios of ED in comparison with never smokers was 1.4 (95% confidence interval 1.3-1.6) for smokers and 1.5 (95% confidence interval 1.3-1.6) for ex-smokers. Duration and intensity of the smoking habit was associated with an increased risk of ED. Among ex-smokers, the risk of ED significantly decreased; with increase in the number of years since the patient quit smoking. CONCLUSION: The study offers an assessment of the association between smoking habit and ED and its potential interaction with other risk factors in diabetic men.

Adult↗

Incidence of erectile dysfunction in Italian men with diabetes.

PURPOSE: We determined the incidence of erectile dysfunction in Italian men with diabetes. MATERIALS AND METHODS: We estimated the incidence of erectile dysfunction, defined as failure to achieve and maintain erection sufficient for satisfactory sexual performance, after 2.8 years of followup in 1,010 men enrolled for a prevalence study of erectile dysfunction in diabetes. RESULTS: Of the 1,010 men 192 (19%) complained of erectile dysfunction. The crude incidence rate of erectile dysfunction was 68 cases per 1,000 person-years (95% confidence interval 59 to 77). The incidence of erectile dysfunction increased with increasing age (10-fold higher for ages 70 to 79 than for 19 to 29 years), duration of diabetes (1.6-fold higher a history of 11 years or greater than for less than 5) and deteriorating metabolic control (1.7-fold higher for hemoglobin A1c greater than 9% than less than 7.5%). Moreover, it was higher in type 2 than in type 1 diabetes (74 versus 45 cases per 1,000 person-years). The relative risk was 1.75, 2.02, 1.97, 1.16, 1.86, 3.79 and 1.52 for associated obliterative arterial disease of the lower legs, ischemic heart disease, renal disease, autonomic neuropathy, sensitive and motor neuropathy, diabetic foot and retinal disease, respectively. Of the characteristics at study enrollment patient age, duration of diabetes, renal disease and hypertension were multivariate predictors of the erectile dysfunction 2.8 years later. CONCLUSIONS: The incidence of erectile dysfunction in Italian men with diabetes at a mean followup of 2.8 years was 68 cases per 1,000 person-years, more than 2-fold that in the Massachusetts Male Aging Study of the general population. The knowledge of this incidence should promote specific preventive and therapeutic interventions for erectile dysfunction in men with diabetes.

Adult↗

Preprandial combination of lispro and NPH insulin improves overall blood glucose control in type 1 diabetic patients: a multicenter randomized crossover trial.

BACKGROUND AND AIM: While lispro insulin has been reported to lower postprandial blood glucose concentrations, less consistent effects have been shown for glycosylated hemoglobin (HbA1c) levels. Aim of this study was to determine whether pre-meal association of NPH, an intermediate-acting insulin, with lispro improves overall glycemic control in type 1 diabetic patients. METHODS AND RESULTS: Eighty-five type 1 diabetic patients were studied in a multicenter randomized comparative (human regular vs lispro insulin) crossover (3-month) study in which NPH insulin was given as a dinner or bedtime injection and at breakfast and lunch if necessary. The number of injections was kept constant: 42% and 58% of patients injected insulin 3 and 4 times per day, respectively. Fasting and preprandial blood glucose levels were similar, while postprandial levels improved after lispro compared to human regular insulin (breakfast: 8.28 +/- 2.39 vs 9.28 +/- 2.72 mmol/l; lunch: 8.33 +/- 2.67 vs 9.06 +/- 2.67 mmol/l, dinner: 8.06 +/- 2.72 vs 9.28 +/- 2.44 mmol/l, ANOVA: p = 0.003). HbA1c also improved after lispro: 8.1 +/- 0.9 vs 8.3 +/- 0.8%, p < 0.05. The rate of hypoglycemia was similar. Patients showed better acceptance of lispro treatment (p < 0.001). CONCLUSIONS: Lispro improves overall blood glucose control in type 1 diabetic patients without increasing the incidence of hypoglycemia. This can be achieved by an optimal combination of lispro insulin with NPH whenever the time intervals between meals are too long.

Adolescent↗

Management of erectile dysfunction in diabetic subjects: results from a survey of 400 diabetes centres in Italy.

We report the results of a survey on erectile dysfunction (ED) conducted in 400 Italian Diabetes Centres in 1998. A questionnaire consisting of 10 items was sent to the Centres recorded by the Italian Association of Diabetologists and the Italian Society of Diabetology; 400 Centres returned the completed questionnaire (58%). Forty-nine percent of the Centres declared that they investigated ED systematically but less than half of them (46%) had done it autonomously. The percentage of Centres performing intracavernous injection (ICI) was 84%. This maneuvre was most commonly performed by diabetologists (61%), followed by urologists (29%) and andrologists (18%) (categories are not mutually exclusive). ICI was also the most common type of treatment (85%), followed by oral (32%) and topic (7%) therapies (categories are not mutually exclusive). Slightly more than half of the interviewed Centres (51%) did not investigate ED routinely, attributing this to structural problems, lack of specific training and the availability of more specialised Centres as the main reasons for this. However, the majority of Centres expressed interest in managing ED. Among the available tests for ED, ICI was the most frequently employed. While most Centres seek the collaboration of external specialists to diagnose ED, the diabetologist is the physician who most frequently performs ICI. We conclude that Italian diabetologists need specific training to reach a greater degree of autonomy in the management of ED in their patients.

Community Health Centers↗

Erectile dysfunction in type 1 and type 2 diabetics in Italy. On behalf of Gruppo Italiano Studio Deficit Erettile nei Diabetici.

BACKGROUND: Several studies reported data on the increased risk of erectile dysfunction (ED) in populations of diabetic men, but few presented data separately for Type 1 and Type 2 subjects. No comparison data for these diabetic subgroups are available with regard to risk factors for ED. METHODS: Eligible for the study were men aged 20-69 years with a diagnosis of insulin-dependent (Type 1) or non-insulin-dependent (Type 2) diabetes who were observed on randomly selected days in 178 diabetes centres in Italy. Erectile dysfunction was defined as a failure to achieve and maintain an erection sufficient for satisfactory sexual performance. RESULTS: The study population consisted of 1383 Type 1 and 8373 Type 2 men. The prevalence of ED increased with age for both groups. After taking into account the effect of age Type 2 men (37/100 men) tend to report ED less frequently than Type 1 men (51/100 men). A significant positive relationship was reported between ED and poor metabolic control and smoking for both Type 1 and Type 2 men, whereas high body mass index (BMI) increased only the risk of ED in Type 1 cases. CONCLUSIONS: The study offers a quantitative estimate of the prevalence of ED and its main risk factors in Type 1 and Type 2 diabetic subgroups.

Adult↗

Functioning human insulinomas. An immunohistochemical analysis of intracellular insulin processing.

Sixty-seven insulinomas were investigated by immunohistochemistry using site-directed antibodies against insulin, proinsulin, chromogranin A, HISL-19, and four proteins directly or indirectly involved in the proteolytic processing of proinsulin: the prohormone convertases PC2 and PC3, carboxypeptidase H (CPH) and 7B2. Results were expressed in a six-grade score according to the frequency of immunoreactive tumour cells. Insulin was expressed by all tumours, appearing in either a diffuse or a polarized pattern and being detected in more than 30% of tumour cells in all cases but three. Proinsulin was also expressed in all tumours, with more than 50% of tumour cells immunoreactive in all cases but 5. It was consistently localized in the Golgi apparatus. In about half the cases, moreover, it also showed diffuse cytoplasmic staining, usually with a very sparse distribution. Trabecular and solid insulinomas did not present specific, homogeneous patterns of insulin immunostaining. However, insulin immunoreactivity was much more abundant in trabecular than in solid neoplasms, being present in virtually all tumour cells (score 6) in 50% and 8% of cases, respectively. Virtually all insulinomas expressed PC2, PC3, CPH and 7B2, usually in 30-100% of tumour cells, with a frequency significantly related to that of insulin. However, detection of PC2 and 7B2 was slightly less frequent than that of PC3 and CPH. In consecutive sections these proteins were found to be mostly co-localized with insulin and chromogranin A but not with proinsulin. They were heavily expressed in all 10 tumours with more than 10% of cells showing cytoplasmic proinsulin immunoreactivity, indicating that the leakage of proinsulin from the Golgi compartment is not associated with faulty expression of converting enzymes and possibly reflects a saturated processing capacity. HISL-19 immunoreactivity was found in both Golgi apparatus and insulin stores, indicating that the relevant antigen is different from all other proteins investigated. These results do not support a defect in expression or localization of proinsulin-processing enzymes in most insulinomas.

Adolescent↗

Erectile dysfunction in diabetic subjects in Italy. Gruppo Italiano Studio Deficit Erettile nei Diabetici.

OBJECTIVE: Our objective was to analyze the prevalence and risk factors for erectile dysfunction (ED) in men with diabetes in Italy in a cross-sectional study. RESEARCH DESIGN AND METHODS: Eligible for the study were men aged 20-69 years with a diagnosis of IDDM or NIDDM who were observed on randomly selected days in 178 diabetes centers in Italy. ED was defined as a failure to achieve and maintain an erection sufficient for satisfactory sexual performance. RESULTS: Of the 9,868 diabetic men interviewed, 3,534 (35.8%) reported ED. The prevalence increased with age, from 4.6% in men aged 20-29 to 45.5% in those aged > or =60 years (test for trend, P = 0.0001). After taking into account the confounding role of age, men with NIDDM reported ED less frequently than did men with IDDM (odds ratio [OR], 0.7; 95% CI 0.6-0.8). In comparison with men reporting diabetes lasting < or =5 years, the ORs for ED were 1.3 and 2.0 for subjects with diabetes lasting 6-10 and 11-30 years, respectively. In comparison with men with good metabolic control, the ORs for ED were 1.7 and 2.3 in men with fair and poor control, respectively. A history of diabetes-related arterial, retinal, or renal diseases and neuropathy was associated with an increased risk of ED. Finally, in comparison with never-smokers, the ORs for ED were 1.5 (95% CI 1.3-1.6) for current smokers and 1.4 (95% CI 1.3-1.6) for ex-smokers. The OR increased with number of cigarettes smoked per day: in comparison with men smoking <12 cigarettes per day, the OR was 1.5 (95% CI 1.3-1.7) for those smoking > or =30 cigarettes day. CONCLUSIONS: The study offers a quantitative estimate of the prevalence of ED and of its main risk factors in Italian men with diabetes.

Adult↗

A multicenter study on the prevalence of diabetic neuropathy in Italy. Italian Diabetic Neuropathy Committee.

OBJECTIVE: The prevalence of neuropathy, a common complication of diabetes, was determined in diabetic patients recruited from 109 outpatient diabetes clinics in Italy. RESEARCH DESIGN AND METHODS: Neuropathy was diagnosed using the Diabetic Neuropathy Index (DNI), a standardized examination developed for use in the outpatient setting. A total of 8,757 diabetic patients were studied, 51.2% men and 48.8% women, with average and median ages of 56 and 58 years, respectively. RESULTS: Of the 8,757 patients, 32.3% had neuropathy, defined as a positive score of > 2 points on the DNI. A total of 2,033 (49.6% men and 50.4% women) were administered the Diabetic Neuropathy Score (DNS), the second component of the screening program, by a neurologist. This component consists of a quantitative neurological examination and nerve conduction studies that together provide a summated score. A total of 335 patients (16.5%) were not neuropathic, and 395 (19.4%) had borderline, 453 (22.3%) mild, 592 (29.1%) moderate, and 258 (12.7%) severe neuropathy. The concordance between a positive score on the DNI and a DNS indicating neuropathy was 83.5%. The severity of neuropathy increased with both age and disease duration. Of patients with neuropathy, 64.1% had an average age between 58 and 59 years with a disease duration between 12.4 +/- 8.4 years (mild neuropathy) and 15.6 +/- 9.7 years (severe neuropathy). CONCLUSIONS: Neuropathy is a common complication of diabetes and, in this study, was present in 32.3% of all patients. An increased awareness of the high prevalence of neuropathy can lead to early therapeutic intervention and possible prevention of later neuropathic complications, such as infection and foot ulcers.

Adult↗

Safety, efficacy, acceptability of a pre-filled insulin pen in diabetic patients over 60 years old.

The aim of the study was to evaluate safety, efficacy and acceptability of a pre-filled insulin pen device (NovoLet) in diabetic patients over 60 years old already treated with insulin administered with conventional syringes. After a run-in period of 2 weeks, 60 patients participated in a randomized cross-over study with two 6-week treatment periods using the insulin pen or conventional syringes. Insulin regimens did not change during the study. Hypoglycaemic episodes did not differ significantly between both kinds of treatment and no severe hypoglycaemia was registered. HbAlc (%) was (mean +/- S.D.) 7.7 +/- 1.2 and 7.9 +/- 1.1 during pen and syringe treatment, respectively. Blood glucose profiles were similar during both treatment modalities except for pre-lunch blood glucose values (mmol/l) lower during pen treatment (8.7 +/- 2.9 vs. 9.2 +/- 2.7, P < 0.01). The insulin dose (U/day) was 31.9 +/- 8.9 (pen) and 32.3 +/- 9 (syringe). 54 patients found the functioning of the insulin pen easy to understand and preferred it for future treatment because the conditions of insulin administration are faster and easier than with conventional syringes. We concluded that the pre-filled insulin pen is safe, efficacious and is highly accepted in over 60 years old diabetic patients.

Adult↗

Use of premixed insulin among the elderly. Reduction of errors in patient preparation of mixtures.

OBJECTIVE: To evaluate the accuracy of elderly patients in their mixing of regular and intermediate insulins, to assess the safety and efficacy of premixed insulins compared with extemporarily mixed insulins, and to determine patients' preferences. RESEARCH DESIGN AND METHODS: We conducted a crossover multicenter study of 5 mo duration. Premixed insulins and patient-mixed, human biosynthetic (rDNA) insulins were used among 64 insulin-treated patients with NIDDM. After a 4-wk run-in period, eligible patients were randomly assigned to treatment 1 (extemporarily mixed insulins) or treatment 2 (premixed insulins) for 8 wk. After that period, the two treatments were crossed for an additional 8-wk period. A blood glucose profile was recorded monthly and HbA1c was measured at the beginning and at the end of each treatment period. An in vitro skills test was performed to assess the accuracy and reproducibility of the patient preparation of insulin doses, and a questionnaire was used to determine their personal preferences for premixed versus extemporarily mixed insulin. RESULTS: In our study, the quality of the metabolic control was the same whether patients used self-mixed or premixed insulin. The differences in blood glucose profiles and HbA1c were negligible between type and periods of treatment. The overall number of hypoglycemic episodes increased during the trial in both groups, but the difference between treatments was not significant. The in vitro skills test, however, indicated that the accuracy in the preparation of insulin doses was significantly higher when patients aspirated from one vial compared with preparation from two vials (P < 0.001). The CVs were 3.7% when drawing up a single dose and 5.0% when preparing a mixture, but the ranges were rather elevated (0.1-20.7 and 0.6-35.8%, respectively). Forty-two patients described the preparation of their daily insulin dose as very easy and 21 described it as easy when using premixed insulins versus 11 and 43, respectively, when using extemporarily mixed insulins (P < 0.001). CONCLUSIONS: While the quality of the metabolic control was the same whether patients used self-mixed or premixed insulin, the in vitro skills test indicated that insulin preparation by elderly patients is highly inaccurate. In some patients, a modification of the contents of the insulin is likely to occur in a few days. The use of premixed insulins should lessen the errors that occur in mixing insulins and from the contamination of the second insulin vial. Draw-up errors could partially account for the lack of improvement of glucose control during the period when patients received premixed insulins. A longer observation period probably is needed to assess appreciable changes in the quality of diabetes control.

Aged↗

Insulin and C-peptide plasma levels in patients with severe chronic pancreatitis and fasting normoglycemia.

The aim of the present study was to evaluate insulin secretion by the pancreatic B cell in a group of patients with severe chronic pancreatitis and without overt diabetes. For this purpose we have measured plasma insulin and C-peptide peripheral levels in the fasting state and after a 100-g oral glucose load in 10 patients with severe chronic pancreatitis and fasting normoglycemia, and in 10 sex-, age-, and weight-matched healthy controls. As compared to normal subjects, patients with chronic pancreatitis showed: (1) significantly higher plasma glucose levels after oral glucose load (area under the plasma glucose curve 1708 +/- 142 vs 1208 +/- 47 mmol/liter X 240 min, P less than 0.005); (2) plasma insulin levels significantly higher at fasting (0.11 +/- 0.008 vs 0.08 +/- 0.005 nmol/liter, P less than 0.01) but not after oral glucose administration (area under the plasma insulin curve 79 +/- 12 vs 88 +/- 16 nmol/liter X 240 min); (3) significantly lower plasma C-peptide concentrations both in the fasting state (0.15 +/- 0.01 vs 0.54 +/- 0.05 nmol/liter, P less than 0.001) and after oral glucose load (area under the plasma C-peptide curve 211 +/- 30 vs 325 +/- 37 nmol/liter X 240 min, P less than 0.05). The finding of diminished plasma C-peptide levels suggests that chronic pancreatitis is associated with an impaired B-cell function even in the absence of overt diabetes. The increased or unchanged plasma insulin levels in spite of decreased plasma C-peptide concentrations indicate that in chronic pancreatitis insulin metabolism is reduced, most likely within the liver.

Blood Glucose↗

Relationship between blood pressure and plasma insulin in non-obese and obese non-diabetic subjects.

In this study, we have measured plasma insulin at fasting and following an oral glucose load and blood pressure after glucose load in 367 (247 non-obese, 120 obese) normotensive and untreated mildly hypertensive subjects. Overall, there was no independent association between fasting plasma insulin levels and blood pressure values. After controlling for age and body weight, a significant relationship between postglucose plasma insulin levels and diastolic blood pressure was found. When non-obese and obese subjects were examined separately, significant relationships were identified between postglucose plasma insulin levels and both systolic and diastolic blood pressure values in the former but not in the latter. A comparison of sex-, age-, and weight-matched hyperinsulinaemic vs normoinsulinaemic subjects showed that the former had significantly higher values of blood pressure only if not obese. These results demonstrate that the plasma insulin response to glucose is independently correlated with blood pressure.

Adult↗

Fractional hepatic extraction of insulin in man: is it constant?

The present study was designed to compare insulin extraction by the liver following oral glucose administrations of different size, in order to evaluate insulin removal by the liver in relation to the insulin exposure, and to the amount of ingested glucose. Insulin secretion by the pancreas was estimated by the measurement of peripheral C-peptide levels, and insulin extraction by the liver by the analysis of peripheral C-peptide to insulin ratios and relations. Ten healthy subjects (5 males and 5 females), aged 16 to 66 yr, with normal bw, and without family history of diabetes mellitus were investigated by means of the administration, on alternate days, of 50 and 150 g oral glucose loads. After the 150 g oral glucose load plasma glucose levels were significantly higher than after the 50 g oral glucose administration: glucose incremental areas of 1.45 +/- 0.12 vs. 0.55 +/- 0.04 mmol/l X min, respectively (p less than 0.001). Similarly, insulin concentrations were significantly higher following 150 g than after 50 g glucose ingestion: insulin incremental areas of 0.52 +/- 0.09 vs. 0.20 +/- 0.04 nmol/l X min (p less than 0.001). Also C-peptide levels were higher after 150 vs. 50 g oral glucose load: C-peptide incremental areas of 1.85 +/- 0.41 vs. 0.64 +/- 0.13 nmol/l X min (p less than 0.01). C-peptide to insulin molar ratios were similar during the two glucose challenge, and averaged 5.25 +/- 0.42 vs. 5.08 +/- 0.50 after 50 and 150 g oral glucose loads, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Influence of the menstrual cycle on glucose tolerance and insulin secretion.

To evaluate the impact of the menstrual cycle on glucose tolerance and insulin secretion, in the present study we have measured the plasma concentrations of glucose, insulin, and C-peptide during a 2-hour oral glucose tolerance test in 110 healthy, nonobese, regularly menstruating women. Fifty-five women were in the follicular phase, and 55 were in the luteal phase of the cycle. The two groups were well matched for age and body weight. Plasma concentrations of glucose, insulin, and C-peptide either in the fasting state or after the oral glucose load did not differ in the two groups. These results suggest that in nondiabetic women the menstrual cycle has no major effect on glucose tolerance and insulin secretion and that the phase of the menstrual cycle should not be considered in programming and interpreting an oral glucose tolerance test.

Adult↗

Relationships between insulin secretion, insulin metabolism and insulin resistance in mild glucose intolerance.

The aim of this study was to evaluate whether the correlation between insulin resistance and peripheral hyperinsulinaemia existing in mild glucose intolerance corresponds to a relationship between insulin resistance and insulin overproduction by the pancreas. In addition, the possibility that insulin resistance is related to insulin metabolism was examined. Twenty five subjects with fasting normoglycaemia and an abnormal glucose response to the oral glucose tolerance test (OGTT) were studied. Insulin secretion by the pancreas was estimated by means of fasting C-peptide levels in peripheral blood. Insulin resistance was estimated by the rate of glucose disappearance from plasma after i.v. insulin injection. Insulin metabolism was estimated indirectly by the C-peptide: insulin molar ratio. A negative correlation was found between the glucose disappearance rate from plasma after i.v. insulin injection and fasting insulin levels (r = -0.677, p less than 0.001), but not fasting C-peptide concentrations (r = -0.164, p = NS). Glucose disappearance rate from plasma correlated positively with the C-peptide: insulin molar ratio (r = 0.626, p less than 0.001). These results suggest that in mild glucose intolerance insulin resistance and insulin secretion by the pancreas are not related phenomena, and that the defect responsible for insulin resistance might also be implicated in the impaired insulin metabolism.

Adult↗