Adding glimepiride to insulin+metformin in type 2 diabetes of more than 10 years' duration--a randomised, double-blind, placebo-controlled, cross-over study.

AIMS: To investigate the effect on glycaemic control of adding glimepiride to on-going treatment with metformin and insulin in patients with known diabetes more than 10 years. METHODS: Glimepiride 4 mg or placebo was added in randomised order for three months with a washout period of 6 weeks. All insulin regimens were allowed. Insulin doses were reduced if considered necessary. Continuous glucose monitoring was performed at the end of each period. RESULTS: Forty-three patients, median age 66 years (46-74), diabetes duration 16 (10-30), BMI 30 kg/m(2) (25-37) and mean HbA1c 7.1% NGSP, (64 mmol/mol IFCC) were randomised. With placebo there was no change in HbA1c while a decrease of 0.6%, (7 mmol/mol IFCC) (P < 0.001), was observed with glimepiride even though insulin doses had to be reduced in 23 patients (median change 29%, range 2-100%). Minor hypoglycaemia was reported but no severe hypoglycaemic event was observed. The ratio between C-peptide/glucose increased significantly (P < 0.001) with glimepiride, both fasting and postprandially and, in a stepwise multiple regression analysis of possible predictive factors for response, a more pronounced decrease in HbA1c was associated with the magnitude of the increment in C-peptide/glucose. Older age was associated with a smaller response. Twenty-nine patients (67%) were defined as responders if this was defined as an HbA1c decrease ≥0.5% (5 mmol/mol IFCC) or an insulin dose reduction ≥20%. CONCLUSIONS: Even after long duration of diabetes, addition of glimepiride to insulin and metformin can be effective in lowering HbA1c and/or reducing the need for exogenous insulin.

Fear of hypoglycaemia in adults with Type 1 diabetes.

AIMS: The aim of this study was to examine the fear of hypoglycaemia and its association with demographic and disease-specific variables in a large and unselective population of adult patients with Type 1 diabetes. METHODS: Questionnaires were sent by post to all patients with Type 1 diabetes who were identified in the local diabetes registries of two hospitals in Stockholm, Sweden (n=1387). Fear of hypoglycaemia was measured using the Swedish Hypoglycaemia Fear Survey, the Worry subscale and the Aloneness subscale. Demographic variables and disease-specific factors were collected from patients' self reports and medical records. Univariate analysis and multiple stepwise linear regression analysis were used in the statistical analyses of the data. RESULTS: Seven hundred and sixty-four (55%) patients participated in the study (mean age 43.3 years and mean HbA(1c) 7.0%, normal <5.0%). The Hypoglycaemia Fear Survey - Worry subscale was significantly associated with frequency of severe hypoglycaemia, number of symptoms during mild hypoglycaemia, gender, hypoglycaemic symptoms during hyperglycaemia and hypoglycaemic unawareness. The Hypoglycaemia Fear Survey - Aloneness subscale was significantly associated with frequency of severe hypoglycaemia, number of symptoms during mild hypoglycaemia, gender, frequency of mild hypoglycaemia, HbA(1c) , hypoglycaemic unawareness and visits to the emergency room because of severe hypoglycaemia. Fear of hypoglycaemia proved to be more prevalent in females and indicated a different pattern between genders in relation to factors associated with fear of hypoglycaemia. CONCLUSIONS: This study identifies the frequency of severe hypoglycaemia as the most important factor associated with fear of hypoglycaemia. Moreover, for the first time, we document gender differences in fear of hypoglycaemia, suggesting that females are more affected by fear of hypoglycaemia than men.

Impaired peripheral micro- and macrocirculation during hemodialysis in uremic patients.

AIM: Acute hemodynamic changes during hemodialysis may jeopardize the peripheral blood circulation in patients with end-stage renal disease (ESRD). The aim of the present study was to investigate the effects of three consecutive hemodialyses on peripheral micro- and macrocirculation in patients with ESRD. METHODS: Twenty patients with ESRD were investigated, i.e. 10 diabetic and 10 non-diabetic patients, before and during three consecutive hemodialysis during one week. Skin microcirculation was evaluated by transcutaneous oxygen tension (tcPO2) at the chest and foot levels, and maximum microvascular hyperemia (MMH) at the foot by laser Doppler fluxmetry before and during local warming of skin to 44 oC. Macrocirculation was measured by systolic and diastolic arm blood pressure (BP), and by systolic toe BP. RESULTS: MMH, tcPO2 (foot) and tcPO2 (chest) decreased significantly (P=0.01) during hemodialysis, and so did systolic arm BP and toe BP (P=0.02). No significant differences were found between the different hemodialysis days, nor between the diabetic and non-diabetic patients. CONCLUSION: The study shows that peripheral micro- and macrocirculation are impaired during hemodialysis in patients with ESRD. The effects of hemodialysis on peripheral blood perfusion are reproducible, and the same reaction pattern was seen in diabetic and non-diabetic patients. Patients with peripheral arterial occlusive disease seem more susceptible to BP reduction during hemodialysis, and in some patients toe BP and tcPO2 (foot) decreased to levels indicating high risk of gangrene.

Decreasing postprandial C-peptide levels over time are not associated with long-term use of sulphonylurea: an observational study.

AIM: The present study aimed to describe changes over 10 years in HbA(1c) and beta-cell function, as assessed by postprandial C-peptide (PP-CPT) and C-peptide/glucose (PP-CPT/glucose) ratio, and to investigate whether treatment with sulphonylurea (SU) exerts a deleterious effect on beta-cell function. METHODS: During 1997-1998, HbA(1c), PP-CPT and PP glucose were measured in 462 patients. Ten years later, 171 of the 341 patients who were still alive were followed-up. RESULTS: HbA(1c) decreased from 7.41 to 6.96% (P=0.002) as treatments were intensified. There was a decrease in both PP-CPT (P<0.001) and PP-CPT/glucose ratio (P=0.063). A multivariable-regression model was used to evaluate the effects on beta-cell function changes, using the following variables as effect modifiers: gender; age; BMI; diabetes duration; baseline PP-CPT/glucose ratio; HbA(1c); GAD-antibody class; and SU treatment (continuously, periodically, never). Baseline PP-CPT/glucose ratio was the most important variable (R(2)=45%; P<0.001) for explaining variations in beta-cell function. An increase in HbA(1c) was associated with a decrease in beta-cell function, and beta-cell function remained unchanged if glycaemic control was improved. Long-term treatment with SU had no effect on long-term changes in beta-cell function (R(2)=0.1%; P=0.894). CONCLUSION: Both HbA(1c) and beta-cell function decreased over 10 years with SU treatment, but such treatment was not associated with a pronounced decline in beta-cell function. These results, however, need to be interpreted with caution, as this was an observational study. Nevertheless, the present study findings do not support the notion that SU, as used in clinical practice, is harmful to beta-cell function.

Dissociated incretin response to oral glucose at 1 year after restrictive vs. malabsorptive bariatric surgery.

AIM: Compare the response to oral glucose of the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) at 1 year after restrictive vs. malabsorptive bariatric surgery. METHODS: Vertical banded gastroplasty (VBG, n = 7) or jejunoileal bypass (JIB, n = 5) was performed in 12 women, aged 26-39 years, with severe obesity [body mass index (BMI) 46.6 +/- 2.3 kg/m(2)]. After 1 year, 75 g glucose was administered and plasma levels of glucose, insulin, GIP and GLP-1 were determined regularly during the following 2 h. RESULTS: At 1 year after operation, reduction in body weight, actual body weight, fasting glucose or insulin, or the glucose and insulin responses to oral glucose did not differ significantly between the groups. Similarly, fasting GIP and GLP-1 levels did not differ significantly between the groups. In contrast, the GIP and GLP-1 responses to oral glucose were different between the groups in a dissociated pattern. Thus, AUC(GIP) was significantly higher after VBG than after JIB (53 +/- 8 vs. 26 +/- 6 pmol/l/min, p = 0.003). In contrast, AUC(GLP-1) was significantly higher after JIB than after VBG (49 +/- 5 vs. 20 +/- 3 pmol/l/min, p = 0.007). CONCLUSIONS: We conclude that at 1 year after bariatric surgery, the two incretins show dissociated responses in that the GIP secretion is higher after VBG whereas GLP-1 secretion is higher after JIB. This dissociated incretin response is independent from reduction in body weight, glucose tolerance or insulin secretion.

Can glycaemic variability, as calculated from blood glucose self-monitoring, predict the development of complications in type 1 diabetes over a decade?

AIMS: Is glycaemic variability an independent risk factor for the development of microvascular complications in addition to average glycaemia, as assessed by glycated haemoglobin (HbA(1c))? In this study, an 11-year follow-up was carried out in patients with type 1 diabetes. The standard deviation of blood glucose (SDBG) concentration, an index of glycaemic variability, was calculated from self-monitored blood glucose data at baseline. METHODS: A total of 100 patients were randomly selected from 442 consecutive type 1 diabetic patients attending our outpatients clinic. SDBG was calculated from 70 measurements taken over a period of four weeks. Onset and progression of micro- and macrovascular complications were recorded over the 11-year follow-up. RESULTS: As expected, the prevalence of complications increased over time. Statistical analyses showed that HbA(1c) was an independent predictor of the incidence (P=0.004) and prevalence (P=0.01) of nephropathy. SDBG was found to be a predictor of the prevalence of peripheral neuropathy (P=0.03), and showed borderline significance in predicting the incidence of peripheral neuropathy (P=0.07). SDBG was also a highly significant predictor of hypoglycaemic unawareness (P=0.001). CONCLUSIONS: We conclude that variability of blood glucose may be important in the development of peripheral neuropathy in patients with type 1 diabetes, and that the nervous system may be particularly vulnerable to glycaemic variability.

Glycaemic responsiveness to long-term insulin plus sulphonylurea therapy as assessed by sulphonylurea withdrawal.

AIMS: To assess the effect of sulphonylurea (SU) in patients with Type 2 diabetes undergoing long-term combination therapy with insulin, by withdrawal of SU, and to identify clinically useful markers of long-term response. METHODS: We studied 25 patients, aged 59-83 years, mean glycated haemoglobin (HbA(1c)) 7.0 +/- 0.6%, who had been treated with SU for 16 years (7-24 years) in combination with insulin for 10 years (6-15 years). After basal measurements, SU was withdrawn. Fasting plasma glucose (FPG) and C-peptide were then monitored every 2-3 days during the following 2 weeks. If FPG increased > 40% or P-glucose exceeded 20 mmol/l, SU was restarted. If neither criterion was met, a clinical follow-up visit with measurement of HbA(1c) was scheduled within 8 weeks. RESULTS: Twenty patients were restarted on SU because of worsening glycaemic control, eight within the first 4 weeks and the remaining 12 at the follow-up visit as their HbA(1c) had increased by 1.1% (range 0.4-2.0%). All these patients were defined as 'SU responders'. The increase in FPG during the initial 2 weeks correlated positively with duration of diabetes (P < 0.01) and duration of SU treatment (P < 0.001). The 'SU responders' had higher levels of basal fasting C-peptide (0.84 +/- 0.44 vs. 0.41 +/- 0.15 nmol/l, P < 0.05), but the variation was wide and none of the measured variables identified 'SU responders'. CONCLUSIONS: In 80% of this group of patients, glycaemic control deteriorated after SU withdrawal despite long duration of SU treatment.

A morning dose of insulin glargine prevents nocturnal ketosis after postprandial interruption of continuous subcutaneous insulin infusion with insulin lispro.

AIM: The aim of this crossover trial was to evaluate the potential of partial substitution of basal insulin with glargine, administered once daily in the morning, to protect against nocturnal ketosis after postprandial interruption of continuous subcutaneous insulin infusion (CSII). METHODS: Seven patients with type 1 diabetes received 4 weeks of treatment with insulin lispro, administered by CSII, and 4 weeks of treatment with CSII and a partial basal replacement dose of insulin glargine administered in the morning. On day 28 of each treatment phase, patients were admitted to the research unit where dinner was served and their usual dinner insulin bolus dose given, after which CSII was discontinued at 7 pm. Plasma (p) beta-hydroxybutyrate and p glucose were measured every hour for 12 h thereafter. RESULTS: Plasma beta-hydroxybutyrate at 7 pm was 0.16+/-0.05 and 0.13+/-0.07 mmol/l with and without glargine, respectively, and increased to 0.17+/-0.10 and 0.60+/-0.3 mmol/l within 6 h (P=0.02). Plasma glucose increased without glargine, from 8.6+/-2.9 to 21.1+/-3.0 mmol/l (P=0.003), but did not rise significantly following glargine (13.6+/-4.7 vs. 12.6+/-5.6 mmol/l; P=0.65). CONCLUSIONS: Partial replacement with a morning dose of insulin glargine protects against the development of ketosis for as much as 12 h after postprandial interruption of CSII. This treatment strategy could, therefore, be useful for patients who are prone to ketosis but, for other reasons, are deemed suitable for CSII.

Nocturnal differences in subcutaneous tissue glucose between forearm and abdominal sites during continuous glucose monitoring in normal subjects.

OBJECTIVE: A number of short-term studies using the continuous glucose monitoring system (CGMS) indicate that improved metabolic control can be observed in patients with type 1 diabetes when CGMS is applied in clinical practice. Data have also accumulated to suggest that spot measurements of glucose performed four times a day would not detect as much as 70% of all hypoglycaemic episodes registered by CGMS. When more frequent reference values were obtained however it was inferred that nighttime hypoglycaemia reported by CGMS may be spurious. As most assessments with CGMS have been utilizing abdominal subcutaneous tissue, we were interested to evaluate whether differences between blood glucose and sensor readings obtained from different sites exist. RESEARCH DESIGN AND METHODS: Two viscometric affinity glucose sensors, applicable to subcutaneous tissue of both forearm and abdomen, were inserted subcutaneously in 12 non-diabetic subjects. Sensors generated glucose data at 3 min intervals and venous blood glucose was determined in duplicates by HemoCue at 15-90 min intervals for 24 hours. Each subject consumed three carbohydrate-rich meals, performed an exercise test, and was observed during nocturnal bed-rest at the research center. RESULTS: The initial decrease of blood glucose during exercise was not fully detected by the sensors. Otherwise, no significant differences between sensor values and blood glucose were observed during day-time. During nocturnal bed-rest abdominal sensor values came approximately 20% lower than blood glucose (P<0.001) and forearm sensor readings. CONCLUSION: It is concluded that a difference between glucose values obtained from abdominal and forearm subcutaneous fat can be observed during nocturnal bed-rest in non-diabetics.

Accuracy of continuous nocturnal glucose screening after 48 and 72 hours in type 2 diabetes patients on combined oral and insulin therapy.

OBJECTIVE: To evaluate the accuracy of nocturnal continuous glucose monitoring by CGMS. RESEARCH DESIGN AND METHODS: A CGMS was inserted in 14 type 2 diabetic patients on combined oral and insulin therapy at altogether 15 occasions. During the second (48 hours) and third (72 hours) night of registration each subject was observed and plasma glucose was analysed seven times during the night by venous sampling and compared to CGMS. These venous values were not used for calibration of the sensor. Pairs of data were analysed using correlation coefficient, Bland-Altman graphs and Clarke Error Grid analysis. RESULTS: 32% of CGMS data did not meet the quality criteria for optimal accuracy and were excluded. A correlation coefficient of 0.80 (p < 0.0001) was seen after 48 hours and a lower coefficient of 0.33 (p = 0.0082) after 72 hours. Bland-Altman analyses demonstrated that the dispersion of the values around the mean of differences was wider after 72 hours as compared to after 48 hours. In the Clark Error Grid analysis 100% of data were within zones A and B after 48 hours, with 60% in zone A. After 72 hours only 44% were in zone A and 7% of data were in the clinically unacceptable zone D. CONCLUSION: The MiniMed Medtronic CGMS has acceptable nocturnal accuracy after 48 hours of registration, but the accuracy thereafter deteriorates with time, implicating that the CGMS thereafter may prove less useful for nocturnal monitoring.

A paracetamol-pasta test for assessing gastric emptying in healthy and diabetic subjects.

Previous studies have shown that the relationship between gastrointestinal symptoms and gastric emptying is weak. Therefore the quantitative assessment of gastric emptying with a relatively simple, non-invasive test would be of considerable clinical value in insulin-treated diabetic patients to identify those with disturbed gastric emptying. The aim of this investigation was to evaluate the inter- and intra-subject variability of a paracetamol-pasta test in healthy subjects and in IDDM patients. Eighteen healthy subjects (8 women) with a mean age of 37 years (range 19-68) and 19 IDDM patients (10 women) with a mean age of 48 years (range 25-62) and mean duration of diabetes of 28 years (range 6-52) were studied on two occasions with an interval of 1 to 4 weeks. After an overnight fast the subjects ingested a standardized pasta meal mixed with 2 g paracetamol in a period of 15 min. Blood samples were drawn at regular intervals after meal intake and analysed for paracetamol (P) and blood glucose. The serum levels of P were significantly lower at 15 min in diabetic patients. The intra-subject coefficients of variation (CV%) of the areas under the serum paracetamol concentration-time curve (AUC) were almost identical in healthy and diabetic subjects, while the intra-subject CV of the P-Tmax was considerably lower in diabetic patients as well as markedly lower than the corresponding inter-subject CV. The inter-subject CVs of all parameters calculated were generally higher in diabetic patients. This study indicates that the assessment of paracetamol absorption kinetics during a paracetamol-pasta test is reproducible in healthy as well as in diabetic subjects. Diabetic patients with non-optimal glucose control and without a case history indicating gastroduodenal motor function disturbances achieve lower serum concentration of P at 15 min and generally display a higher inter-individual variability indicative of subclinical disturbances of gastric emptying in this group of patients.

A repeated cross-sectional survey of severe hypoglycaemia in 178 Type 1 diabetes mellitus patients performed in 1984 and 1998.

AIMS: To study the prevalence of severe hypoglycaemia (SH) in relation to risk factors in Type 1 diabetic (T1 DM) patients over a period of 14 years. METHODS: We performed a cross-sectional survey of a cohort of 178 T1 DM patients registered at our out-patient clinic in 1984 to be repeated in 1998. An identical questionnaire was sent to the patients in the beginning of 1985 and 1999, respectively, regarding the problem of SH in the preceding year. Additional clinical data were obtained from the patients' medical records on insulin treatment, long-term complications, morbidity, and co-medication. RESULTS: At follow up, the use of multiple insulin injection therapy had increased from 71% to 98% (P < 0.001) and daily self-monitoring of blood glucose (SMBG) from 17% to 48% (P < 0.001). Twenty-seven percent were treated with direct-acting insulin analogues in 1998. An increasing number of patients reported unawareness of hypoglycaemia, 54% vs. 40% (P < 0.01), and nocturnal events were more frequent, 83% vs. 76% (P < 0.05). The prevalence of SH had increased from 17% to 27% (P < 0.05) and a slight decrease of HbA1c, 7.6% to 7.4% (P < 0.05) was documented. CONCLUSION: We conclude that despite more frequent use of multiple injection therapy and SMBG, the prevalence of SH has increased by > 50% over 14 years. A multiple logistic regression analysis of risk factors for SH explained less than 10% of the variance, implicating only unawareness of hypoglycaemia and HbA1c.

Improved beta cell function after short-term treatment with diazoxide in obese subjects with type 2 diabetes.

OBJECTIVE: Our aim was to distinguish beneficial effects of B-cell rest from other effects of correction of hyperglycaemia. For this purpose we used diazoxide which reversibly blocks insulin secretion. MATERIAL AND METHODS: Eight obese (age 53 +/- 1 yr: BMI 33 +/- 2 kg/m2: 4 females) type 2 diabetic patients with poor metabolic control (HbA1c 8.7 +/- 0.9% ref.<5.2%) were studied twice after a randomly ordered treatment period of five days of intensive i.v. insulin treatment alone or i.v. insulin with peroral diazoxide (300 mg/day, divided into 3 doses). The glycaemic control was not altered between the two treatment periods. Insulin secretion was measured in response to i.v. glucose and arginine. RESULTS: Insulin infusion was used to achieve close to identical degrees of glycaemia during the two treatment periods. Previous treatment with diazoxide was associated with a moderate 1.9 +/- 0.6 fold rise in insulin response to intravenous glucose (p=0.04) and 1.6 +/- 0.4 fold increased glucose potentiation of arginine-induced insulin secretion (GPAIS) (p=0.04). Conversely, after insulin alone there was no response to i.v. glucose and no change in GPAIS. CONCLUSIONS: Short-term diazoxide treatment improved important parameters of B-cell function and these effects could be dissociated from confounding effects of changes in glycaemia. Consequently, the results indicate beneficial effects of B-cell rest.

Improved blood glucose variability, HbA1c insuman Infusat and less insulin requirement in IDDM patients using insulin lispro in CSII. The Swedish Multicenter Lispro Insulin Study.

The aim of the study was to compare lispro (LP) and Insuman(R) (I) insulin in continuous subcutaneous insulin infusion (CSII) therapy with respect to blood glucose control as expressed by the standard deviation of blood glucose (SD(BG) ) and HbA(1c) and to monitor the well-being (WBQ) and treatment satisfaction (DTSQ) parameters during such treatment. Forty-one IDDM patients who had used CSII for at least 6 months participated in an open-label, randomized, cross-over, multicenter study for 4 months (2 months LP and 2 months I or vice versa). Boluses with LP were given 5 min before each meal and with I 30 min before each meal. During LP administration compared with I, the SD(BG) of all blood glucose values (3.6 mmol/l vs. 3.9 mmol/l, p=0.012), as well as the SD(BG) of the postprandial, blood glucose values (3.6 mmol/l vs. 4.0 mmol/l, p=0.006), were significantly reduced. The HbA(1c) was significantly lower during LP administration (7.4% vs. 7.6%, p=0.047). The incidence of hypoglycemic events per 30 days (capillary blood glucose<3.0 mmol/l and/or symptoms) did not significantly differ between LP and I (9.7 vs. 8.0 per month, p=0.23). The total amount of daily insulin was slightly but significantly lower with LP, compared to I (38.0 IU vs. 40.3 IU, p=0.004). There was no treatment effects of LP compared to I concerning WBQ and DTSQ. It is concluded that in CSII therapy LP is superior to I with respect to the stability of blood glucose control, a lower HbA(1c), a less insulin requirement without increasing the frequency of hypoglycemia.

Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients.

The glycaemic and hormonal responses to a hypoglycaemic event induced by an i.v. bolus of insulin was studied in seven type 1 diabetic patients treated first with continuous subcutaneous insulin infusion (CSII) and subsequently with continuous intraperitoneal insulin infusion (CIPII). Arterialised blood glucose and venous hormonal responses were analyzed. HbA1c was improved by CIPII. Although a regimen of a higher basal insulin infusion rate was applied during CIPII the basal peripheral venous insulin levels were lower. The i.v. bolus of insulin resulted in hypoglycaemia in both tests but was more pronounced during the CSII test expressed as a smaller area under the curve (AUC) for the first hour (13.0 +/- 2.3 vs. 13.7 +/- 1.2 mmol l(-1) h(-1), p=0.016, CSII vs. CIPII). The hypoglycaemia resulted in a significant and similar increase in the plasma levels of adrenaline, cortisol and growth hormone in both experiments. A significant increase in the glucagon level was only observed during CIPII. The incremental glucagon response was also significantly more pronounced in the CIPII test expressed as maximal responses (7.5 +/- 3.0 vs. 17.0 +/- 3.1 pg ml(-1), p =0.048, CSII vs. CIPII) as well as incremental AUC (5.1 +/- 12.0 vs. 44.4 +/- 13.2 pg ml(-1) h(-1), p =0.027, CSII vs. CIPII). It seems that CIPII in type 1 diabetic patients could improve the glucagon release to hypoglycaemia. This observation may contribute in explaining why CIPII is associated with a lower incidence of hypoglycaemia in spite of an improvement in metabolic control.

Pyridine nucleotides in glucose metabolism and diabetes: a review.

Nicotinamide adenine dinucleotide (NAD) and its derivatives NADH, NADP and NADPH have regulatory functions in the generation of triose phosphates and pyruvate from glucose. In many studies of the influence of the diabetic state on relationships between pyridine nucleotide and glucose metabolism, the focus has been on the sorbitol pathway. Less attention has been paid to other aspects of the role of pyridine nucleotides in pyruvate formation from glucose, in particular the effects of the NAD precursors nicotinamide and nicotinic acid on glucose metabolism. This paper reviews current knowledge of the involvement of pyridine nucleotides and their precursors in glucose catabolism in the normal and diabetic state. Reference is also made to the following three current hypotheses for mechanisms underlying diabetic microangiopathy: 1. Chronic glucose overutilization, caused by hyperglycemia, in tissues which lack insulin receptors and therefore are freely permeable to glucose. 2. Enhancement of sorbitol pathway activity with an ensuing decrease in the ratio of NAD/NADH. 3. Enhanced utilization of both glucose and pyridine nucleotides in formation of triose phosphates and pyruvate. Therapy with NAD precursors like nicotinamide might have corrective effects on these proposed biochemical aberrations, thereby retarding progression of microangiopathy.

Circulating insulin inhibits glucagon secretion induced by arginine in type 1 diabetes.

OBJECTIVE: To evaluate if insulin has a suppressive effect on the glucagon secretion stimulated by arginine in type 1 diabetes. RESEARCH DESIGN AND METHODS: The alpha-cell response to an i.v. bolus of arginine (150mgkg(-1)) followed by an infusion of arginine (10mgkg(-1)min(-1)) was studied in random order during either low dose infusion (LDT) or high dose infusion (HDT) of insulin in ten patients with type 1 diabetes. The blood glucose level was clamped at an arterialized level of 5mmoll(-1) by a variable infusion of glucose. Venous C-peptide, glucagon, growth hormone, and insulin were analyzed. RESULTS: The mean plasma concentration of insulin was four times higher during the HDT. The C-peptide level did not differ between the LDT and the HDT. During the LDT in response to arginine the blood glucose level increased from 5.0 to 5.8mmol l(-1) although the glucose infusion was markedly reduced, while no change was seen during the HDT. A significantly smaller increase in the glucagon levels during the HDT was seen (area under the curve of 413+/-45 vs 466+/-44pgml(-1)h(-1), P=0.03) while the growth hormone levels were almost identical. CONCLUSION: This study demonstrates that a high level of circulating insulin exerts an inhibitory effect on the glucagon response to arginine in type 1 diabetes. Thus, the suppressive effect of insulin on the glucagon release from the alpha-cell seems to be general and not only dependent on stimulation by hypoglycemia.

A randomised study evaluating the effects of cisapride on glucose variability and quality of life parameters in insulin-dependent diabetes mellitus patients.

This study evaluated the effect of cisapride on glycaemic control, well-being and treatment satisfaction in insulin-dependent diabetes mellitus (IDDM) patients with documented moderate to severe glycaemic instability. Thirty-seven patients with glycaemic instability were included in a randomized, double-blind, placebo-controlled, cross-over study. Patients were instructed to take cisapride 10 mg q.i.d. or placebo tablets q.i.d. (15 to 30 min before each of the three main meals and before bedtime) for two periods of four weeks. The first treatment period was followed by a wash-out period of four weeks, with placebo treatment. Patients measured blood glucose with a glucometer before breakfast, lunch, dinner, 90 min after dinner and before bedtime every two days. After each treatment period, glucose data were collected from the glucometer to calculate the standard deviation (SDBG) of self-monitored blood glucose (SMBG). Questionnaires designed to measure well-being and treatment satisfaction were also completed initially and after each of the two treatment periods. There were no treatment effects of cisapride compared to placebo with respect to SDBG, mean glucose, percentage of extremes, number of hypoglycaemic episodes, insulin requirement, insulin variability, well-being, or treatment satisfaction. Cisapride 10 mg q.i.d. given for four weeks did not affect diabetic control or well-being and treatment satisfaction in a group of IDDM patients with glycaemic instability, i.e. a standard deviation of blood-glucose > 3.9 mmol/l.

Oral glibenclamide suppresses glucagon secretion during insulin-induced hypoglycemia in patients with type 2 diabetes.

Intensifying pharmacological therapy in patients with type 2 diabetes increases the risk of hypoglycemia and often requires the simultaneous use of more than one agent. Combining insulin and sulfonylurea is an effective and frequently used therapy in such patients. However, sulfonylurea derivatives have been shown to affect the release of glucagon, indicating a possible effect of such therapy on hormonal counterregulation to hypoglycemia. Thirteen patients receiving combined therapy were studied on two occasions: 1) after a wash-out period of glibenclamide (-GLIB), and 2) after resuming combined treatment for 6 months (+GLIB). We performed nonstep-wise, hyperinsulinemic hypoglycemic clamps using a constant i.v. insulin infusion and clamping blood glucose at 2.7 mmol/L (48 mg/dL) for 60 min. C Peptide levels were significantly higher during + GLIB, but no significant differences were seen in peripheral plasma insulin levels (+GLIB mean +/- SD, 70 +/- 17 mU/L vs. -GLIB, 75 +/- 14; P = 0.26). Epinephrine responses were similar in the two tests, but when glibenclamide was present the glucagon response was smaller, both the peak value (P = 0.016) and the incremental area under the curve (P = 0.011) as well as the total area under the curve (P = 0.016). These results suggest that intraislet insulin secretion is of importance for the alpha-cell responsiveness to hypoglycemia in these patients.