Secondary failure of oral hypoglycaemic agents in lean patients with type 2 diabetes mellitus: insulin sensitivity, insulin response to different stimuli, and the role of cyclic-AMP.

The aim of this study was to evaluate the insulin (IRI) response to different stimuli and insulin sensitivity in Type 2 diabetic patients responsive to oral hypoglycaemic agents (OHA) and in Type 2 diabetic patients with secondary failure of OHA (SF), all patients being of normal body weight (relative body weight less than 120%), and the possible role of cyclic AMP in the reduced IRI release. SF patients, without islet cell antibodies (ICA), with hyperglycaemia lasting more than 3 months, underwent tests with i.v. tolbutamide (n = 21), i.v. glucose (n = 14), i.v. glucagon (n = 19), i.v. arginine infusion (n = 18); the arginine infusion was repeated in 12 patients during administration of aminophylline, an inhibitor of phosphodiesterase. The same tests were performed in groups of 8 to 15 OHA patients and in groups of 6 to 17 healthy subjects. During all the tests, blood glucose levels were higher in SF patients, than in OHA patients and in healthy subjects. Both SF patients and OHA patients had no IRI response to glucose; SF patients, in contrast to OHA patients, had a reduced IRI response to tolbutamide and to glucagon. The IRI response to arginine was not different in OHA, in SF patients and in healthy controls, but was significantly enhanced by aminophylline only in healthy controls. Insulin infusions (1.66 mU/Kg/min for 90 min) were performed in OHA patients and in SF patients at blood glucose levels of 150 and of 250 mg/dl: during the last 60 min, the amount of glucose metabolized (M), and the insulin sensitivity (M/I) index were greater in OHA than in SF patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Association between chlorpropamide-alcohol flushing and fast acetylator phenotype in type I and type II diabetes.

Different prevalences of chlorpropamide alcohol flushing (CPAF) have been reported by different authors in either type I or type II diabetics or in normal subjects and this could be due to different methodological approaches or to different criteria of evaluation of CPAF. Previous studies in small series of patients have also suggested the existence of an association between type I diabetes and the fast acetylator phenotype (AP). The first aim of this study was to find reliable criteria for the assessment of CPAF. The second was to evaluate the prevalence of CPAF and of AP in a large series of type I and type II diabetics; and the third was to evaluate possible associations of CPAF and AP. AP and CPAF were evaluated separately in 256 diabetics (110 with type I and 146 with type II diabetes) and in 183 diabetics (74 with type I and 109 with type II diabetes), respectively. In 156 of these subjects, the two markers were evaluated together. The occurrence of CPAF was studied by subjective and objective assessment and by thermographic recording; CPAF was quantified by the differential value of skin temperature increase [delta T(C-P)] and by the value of differential speed of ascent, expressed in angle-degrees [delta a(C-P)], after treatment with placebo and with chlorpropamide. The fast AP was more frequent in type I than in type II diabetics, was not related to family history of diabetes, sex of the patients, age at onset and duration of diabetes or metabolic control. The most reliable assessment of CPAF was represented by thermographic recording of speed of ascent of skin temperature. CPAF was more frequent in females than in males, more frequent in diabetics than in healthy controls, similarly frequent in type I and in type II diabetes and showed no relationship with family history of diabetes, age at onset, duration of diabetes or metabolic control. An association between fast AP and CPAF was found in type II, but not in type I diabetics: fast acetylators were more frequently CPAF-positive, while slow acetylators were more frequently CPAF-negative. In addition, a linear relationship was found between rate of acetylation and speed of ascent of facial skin temperature after chlorpropamide and alcohol in type II diabetics, not in type I diabetics. The meaning of this association is not clear and deserves further investigations.

Genetic and metabolic risk factors for the development of late complications in type I (insulin-dependent) diabetes.

The genetic background seems to be involved in the development of type I diabetes and it might also be involved in the development of diabetic complications, but studies carried out so far have yielded conflicting results. The aim of this study was to evaluate the influence of some genetic markers and metabolic factors in the development of late diabetic complications. One hundred and twenty-seven patients (69 males, 58 females) with type I diabetes were evaluated for ABO and Rh blood groups, chlorpropamide alcohol flush (CPAF) and acetylator phenotype (AP) as well as for life-habits (smoking, alcohol use, diet and drug compliance), metabolic indexes (M-value, HbA1, cholesterol and triglyceride levels) and late complications of diabetes [coronary heart disease (CHD), arterial hypertension (AH), retinopathy and nephropathy]. Diabetic patients were more frequently fast acetylators and CPAF positive than controls and CPAF was more frequent among females than among males. None of the genetic markers used in this study appeared as a risk factor for the development of diabetic complications. At multiple logistic analysis different risk factors appeared for each microangiopathic complication. For retinopathy: female sex, duration of disease and triglyceride levels; for nephropathy: male sex, cholesterol levels and hypertension. These risk factors have already been recognized in previous studies, while the genetic markers evaluated in our study do not identify a greater or smaller risk for the development of late complications.

Risk factors for micro- and macroangiopathic complications in type 2 diabetes: lack of association with acetylator phenotype, chlorpropamide alcohol flush and ABO and Rh blood groups.

Genetic markers would be useful to study the transmission of type 2 diabetes and to identify patients with enhanced risk of development of late diabetic complications. The aim of this study was to evaluate the influence of selected possible genetic markers on the development of diabetic complications. One hundred and eighty patients with type 2 diabetes (79 males, 101 females) were therefore studied with respect to ABO and Rh blood grouping and chlorpropamide alcohol flush (CPAF) and acetylator phenotype status, in addition to life style (smoking, dietary, alcohol and drug taking habits) and metabolic indexes (HbA1, M-value, serum cholesterol, serum triglycerides), with regard to late complications coronary heart disease (CHD), arterial hypertension (AH), peripheral vascular disorders (PVD), retinopathy and nephropathy. None of the genetic markers considered appeared to be associated with diabetic complications. Multiple logistic analysis identified different risk-factors for each complication: AH and age for CHD; hyperlipidaemia for AH; age of patients for PVD; duration of diabetes for retinopathy; AH for nephropathy. It is concluded that the possible genetic markers evaluated in this study do not identify a higher or lower risk for late complications. On the contrary, most of the risk factors identified support previous studies. Active correction of these risk-factors might improve the overall prognosis of patients with type 2 diabetes.

Secondary failure to oral hypoglycaemic agents in non-obese patients with non-insulin-dependent diabetes is related to reduced insulin release.

The frequency of secondary failure to oral hypoglycaemic agents (OHA) in patients with non-insulin dependent diabetes (NIDDM) is still unknown, despite more than 30 years of use of OHA. The term secondary failure should be limited to patients who, despite maximal dosages of OHA and despite full compliance with diet and therapy, are no longer controlled and require insulin to obtain an acceptable glucose metabolism. We evaluated 248 out-patients, either on OHA, or on insulin because of poor metabolic control with OHA, in order to assess duration of treatment with OHA since diagnosis, by means of actuarial curves (Mantel-Cox test). Patients with low relative body weight (RBW less than or equal to 100) experienced secondary failure earlier and more often than obese patients (RBW greater than 120) or overweight (RBW 101-120) patients. In 66 of the above out-patients, 33 OHA-treated and 33 insulin-treated, matched for age at onset and duration of disease, islet-cell-antibodies (ICA) and C-peptide release at fasting, 6 min after i.v. glucagon and post prandially were evaluated. Only among lean and overweight patients, was C-peptide release significantly lower in insulin-treated than in OHA-treated patients; differences disappeared in obese patients. ICA were found in only 7 patients (10.6%). HLA phenotype was different from that of healthy blood donors for the loci HLA B5, B13, CW4, with no differences between OHA-treated and insulin-treated patients. These data indicate that secondary failure is more frequent in lean patients with NIDDM, and is related to reduced insulin release.

Impairment of lymphocyte suppressive system in recent onset insulin-dependent diabetes mellitus. Correlation with blood glucose and serum insulin levels.

In a previous study, we observed an impairment of the theophylline-induced suppressive system in recent onset IDDM patients, and demonstrated also a correlation with metabolic derangement. The aim of this study was to better investigate the relationship between theophylline sensitivity (ThS) and blood glucose/plasma insulin levels in recent onset IDDM patients subjected to preprogrammed variations by an insulin/glucose clamp with artificial pancreas. Eight patients were studied within 8 weeks from the onset of IDDM. ThS was evaluated as the ability of theophylline to inhibit blastogenic response of peripheral blood lymphocytes (PBL) to Concanavalin A (ConA), after 120 min preincubation of the cells. All patients were connected to an artificial pancreas. Through i.v. continuous insulin infusion (0.02 U/kg/h) and/or i.v. continuous glucose and saline infusion, the following experimental conditions, lasting at least 1h, were obtained: T1: relative euglycemia and normal insulinemia; T2: relative euglycemia and hyperinsulinemia; T3: hyperglycemia and normal insulinemia; T4: hyperglycemia and hyperinsulinemia. ThS was maintained in 6/8 patients at T1 and in 8/8 patients at T4. ThS was lost in 4/8 patients at T2 and T3. These data suggest that the loss of ThS induced by hyperglycemia can be corrected by hyperinsulinemia, and that it is maintained when euglycemia is accompanied by hypoinsulinemia. It is lost when these two parameters lose their interrelationship.