Decreased insulin sensitivity in offspring whose parents both have type 2 diabetes

Offspring of two Type 2 diabetic parents have a high prevalence of diabetes and impaired glucose tolerance. Studies in normoglycaemic offspring have shown abnormal insulin responses. Twenty-four non-obese offspring having normal oral glucose tolerance were investigated by the insulin tolerance test for abnormalities of insulin sensitivity. Plasma insulin responses were measured during an oral glucose tolerance test. Although the plasma glucose responses during the OGTT were similar to the control values, the corresponding insulin responses were higher. The mean area under the insulin curve was 121 +/- 29 (+/- SD) mU l-1 h in the control subjects and 203 +/- 73 mU l-1 h in the offspring (p less than 0.001). The mean KITT value in the offspring was 4.3 +/- 1.9 min-1 x 100 which was significantly lower (p less than 0.01) than the value of 6.2 +/- 2.0 min-1 x 100 in the control subjects. The results suggest that some offspring of two Type 2 diabetic parents have low insulin sensitivity and the presence of hyperinsulinism may be a compensatory phenomenon.     

Insulin supplement in type 2 diabetic patients with secondary failure to oral agents ameliorates hepatic and peripheral insulin sensitivity but not insulin secretion

In order to investigate the mechanism of amelioration of metabolic abnormalities with supplementary doses of insulin, islet B-cell function and insulin sensitivity were measured in 10 patients with Type 2 diabetes in secondary failure to oral agents. A small dose of ultralente insulin (0.26 +/- 0.07 U kg-ideal-body-weight-1) was added in the morning before breakfast. After 3 months insulin therapy and progressive improvement of metabolic control (HbA1 from 10.5 +/- 0.4 to 9.0 +/- 0.3% at the end of insulin treatment, p less than 0.001), basal C-peptide and incremental area during an oral glucose tolerance test were unchanged. In vivo peripheral insulin sensitivity (euglycaemic clamp with insulin infusion of 40, 160, and 600 mU m-2 min-1, respectively) was significantly improved (glucose requirement: to 4.7 +/- 1.0 from 3.0 +/- 0.6 mg kg-1 min-1, p less than 0.05 at first insulin level; to 10.8 +/- 0.5 from 9.3 +/- 0.7 mg kg-1 min-1, p less than 0.01 at second level; to 13.3 +/- 0.6 from 11.8 +/- 0.8 mg kg-1 min-1, p less than 0.025 at third level). Basal hepatic glucose production was also significantly reduced (from 4.3 +/- 0.4 to 3.3 +/- 0.3 mg kg-1 min-1, p less than 0.05), and residual glucose production further suppressed after insulin supplement (from 1.1 +/- 0.4 to 0.3 +/- 0.2 mg kg-1 min-1 after 120 min at 100 mU l-1 plasma insulin, p less than 0.05). Specific insulin binding to mononuclear leucocytes was unchanged (from 3.1 +/- 0.3 to 3.5 +/- 0.3%, NS).     

Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus.

Improved blood glucose control by insulin treatment in patients with Type 2 (non-insulin dependent) diabetes mellitus increases the risk for hypoglycaemic episodes. Our objective was to investigate if hypoglycaemia causes electrocardiographic changes and cardiac arrhythmias in patients with Type 2 diabetes. Six insulin-treated patients with Type 2 diabetes and no known cardiac disease took part in the study. Hypoglycaemia was induced by insulin infusion aiming at a plasma glucose less than or equal to 2.0 mmol l-1 or hypoglycaemic symptoms. All patients experienced hypoglycaemic symptoms. The median lowest arterial plasma glucose was 2.0 mmol l-1. Arterial plasma adrenaline concentration increased from 0.4 +/- 0.1 (mean +/- SE) to 6.9 +/- 0.3 nmol l-1 (p less than 0.001) while serum potassium was lowered from 4.1 +/- 0.3 mmol l-1 to 3.5 +/- 0.2 mmol l-1 (p less than 0.001). The heart rate increased significantly during hypoglycaemia except in one patient who developed hypoglycaemic symptoms and a severe bradyarrhythmia at a plasma glucose of 4.4 mmol l-1. One patient developed frequent ventricular ectopic beats during hypoglycaemia while four patients showed no arrhythmia. ST-depression in ECG leads V2 and V6 was observed during hypoglycaemia in five patients (p less than 0.05) and four patients developed flattening of the T-wave. In conclusion, the study supports the hypothesis that hypoglycaemia in patients with Type 2 diabetes may be hazardous by causing cardiac arrhythmias.     

Short-term metabolic effects of the ACE-inhibitor benazepril in type 2 diabetes mellitus associated with arterial hypertension.

To assess the short-term metabolic effects a long-acting non-sulphydryl ACE-inhibitor benazepril on glycaemic control in Type 2 diabetes mellitus and arterial hypertension, 10 hypertensive diabetic patients treated with glibenclamide were studied in a double-blind, crossover fashion over two 10-day periods in which either benazepril (10 mg/day) or placebo was given. At the end of the 10 day treatment, both blood pressure and plasma glucose concentrations were lower after benazepril versus placebo (benazepril, blood pressure: 143 +/- 11/83 +/- 5 mmHg, plasma glucose: 7.1 +/- 1.2 mmol/l; placebo: blood pressure: 157 +/- 10/99 +/- 2 mmHg, plasma glucose: 8.2 +/- 1 mmol/l, p < 0.05). In response to an oral glucose tolerance test combined with 1 mg intravenous glibenclamide, plasma glucose levels were lower after benazepril versus placebo (0-460 min: 8.4 +/- 0.8 versus 10.5 +/- 0.9 mmol/l, p < 0.05), whereas plasma insulin, C-peptide and glibenclamide concentrations were not different. It is concluded that a short-term administration of benazepril in Type 2 diabetes mellitus reduces blood pressure and improves blood glucose control, most likely by decreasing insulin resistance.     

Effects of chronic angiotensin converting enzyme inhibition on glucose tolerance and insulin sensitivity in essential hypertension.

The relation between the renin-angiotensin-aldosterone (RAA) system and carbohydrate metabolism and insulin sensitivity in essential hypertension has not been investigated systematically. Twenty nondiabetic patients (age, 49 +/- 1 years; body mass index (BMI), 26.1 +/- 0.4 kg/m2) with essential hypertension (blood pressure, 155 +/- 3/105 +/- 1 mm Hg) received an oral glucose tolerance test (OGTT) at the end of a 1-month placebo period and again monthly during 3 months of angiotensin converting enzyme (ACE) inhibition (cilazapril, 5 mg/day). Furthermore, a two-step euglycemic insulin clamp was performed after placebo and again at the end of treatment. Blood pressure fell by 7 +/- 4/10 +/- 3 mm Hg (p less than 0.001), while BMI remained stable. On the euglycemic clamp, insulin-mediated (plasma insulin, 470 pM) whole body glucose use averaged 42.5 +/- 1.6 mumol.min-1.kg-1 before and 43.6 +/- 1.9 after ACE inhibition (p = NS). Substrate concentrations and oxidative rates and energy expenditure (as estimated by indirect calorimetry) were not altered by ACE inhibition, either in the fasting state or in response to insulin. In contrast, oral glucose tolerance was significantly (p less than 0.05) improved after treatment (area under OGTT curve (AUC), 240 +/- 24 versus 282 +/- 23 mmol 2 hr.l-1). The latter change was associated with enhanced (+16%, p less than 0.05) insulin responsiveness to glucose (estimated as the insulin AUC divided by the glucose AUC) throughout the 3 months of ACE inhibition. At baseline, both the OGTT and the clamp had a marked hypokalemic effect (mean decrements in plasma potassium of 0.75 +/- 0.05 and 0.92 +/- 0.05 mmol/l, respectively) in association with plasma aldosterone reductions of 30% and 50%. Chronic ACE inhibition caused a further 20% (p less than 0.03) lowering of plasma aldosterone concentrations but attenuated insulin-induced hypokalemia. Plasma sodium, which was unaltered by the pretreatment tests, fell during the posttreatment tests (by 3 mmol/l, p less than 0.001). In the urine, the ratio of the fractional excretion of potassium to that of sodium was decreased by both oral glucose (-22%, p less than 0.01) and ACE inhibition (-21%, p less than 0.001). Higher plasma potassium levels before treatment predicted a better blood pressure response to ACE inhibition (r = 0.60, p less than 0.005).(ABSTRACT TRUNCATED AT 400 WORDS)     

High plasma insulin and triglyceride concentrations and blood pressure in offspring of people with impaired glucose tolerance

The plasma glucose and insulin response to an oral glucose challenge, fasting plasma lipid concentration, and blood pressure were compared in 13 offspring of parents previously diagnosed as having impaired glucose tolerance (IGT) and 13 offspring of parents previously shown to have normal glucose tolerance. The parents with IGT had higher plasma glucose, insulin and triglyceride concentration, and blood pressure than parents with normal glucose tolerance. The two groups of offspring were young and non-obese, and similar in terms of age, gender distribution, and body mass index. However, the total integrated plasma insulin response during a 75 g oral glucose tolerance test was significantly higher (p less than 0.05, Student's t-test) in offspring of parents with IGT (718 +/- 71 pmol l-1 h) than in the subjects whose parents had normal glucose tolerance (524 +/- 47 pmol l-1 h). In addition, serum triglyceride concentration was somewhat higher in offspring of parents with IGT (1.17 +/- 0.11 vs 0.92 +/- 0.08 mmol l-1, 0.10 greater than p greater than 0.05), as were both systolic (132 +/- 5 vs 118 +/- 3 mmHg, p less than 0.05) and diastolic (79 +/- 3 vs 70 +/- 2 mmHg, p less than 0.05) blood pressure. Demonstration of similar abnormalities in plasma insulin response to glucose and blood pressure regulation in patients with IGT and in their offspring is consistent with the view that these changes have a genetic component.     

Effects of metformin on glucose, insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose tolerance test criteria.

The effect of metformin treatment was studied in nine patients with mild (fasting plasma glucose concentration less than 7.5 mmol.l-1) non-insulin-dependent diabetes mellitus (NIDDM) and fasting plasma triglyceride (TG) concentration greater than 2.0 mmol.l-1. Individuals were studied before and three months after receiving 2.5 g/day of metformin. Mean hourly plasma glucose concentration from 8 AM to 4 PM (7.5 +/- 0.5 vs 6.5 +/- 0.4 mmol.l-1, p less than 0.001), as well as glycosylated hemoglobin levels (7.0 +/- 0.5 vs 6.2 +/- 0.2%, p less than 0.02) were significantly lower following metformin treatment. The improvement in glycaemic control was not associated with an improvement in insulin stimulated glucose disposal as measured by the glucose clamp technique. Mean hourly day-long concentrations of plasma insulin (519 +/- 81 vs 364 +/- 64 pmol.l-1, p less than 0.001), FFA (502 +/- 45 vs 460 +/- 35 mu mol.l-1, p less than 0.01), and triglyceride (3.60 +/- 0.33 vs 3.02 +/- 0.31 mmol.l-1, p less than 0.001) concentrations were significantly lower following three months of metformin treatment. Finally, fasting plasma TG concentration, very low density lipoprotein (VLDL)-TG, and VLDL-cholesterol concentrations were significantly decreased, while high density lipoprotein (HDL)-cholesterol concentration was significantly increased following metformin therapy. Thus, metformin administration to individuals with NIDDM, who did not have significant fasting hyperglycaemia, led to a decrease in plasma glucose, insulin, FFA, and TG concentration, and an increase in plasma HDL-cholesterol concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of metformin on adipocyte insulin action and metabolic control in obese subjects with type 2 diabetes

To investigate the mechanisms of action of metformin, insulin receptor binding and the activity of several insulin-controlled metabolic pathways were measured in adipocytes taken from 10 obese Type 2 diabetic patients treated for 4 weeks with either metformin (0.5 g x 3 daily) or matching placebo using a double-blind crossover design. Metformin therapy was associated with a significant fall in serum fructosamine levels (3.1 +/- 0.4 vs 2.8 +/- 0.4 mmol l-1, p less than 0.02) as well as fasting (10.8 +/- 2.4 vs 9.4 +/- 2.1 mmol l-1) and daytime (11.5 +/- 2.4 vs 10.0 +/- 2.2 mmol l-1) plasma glucose concentrations (p less than 0.05). Fasting and postprandial plasma levels of C-peptide and insulin were unchanged. While fasting plasma lactate concentrations remained unaltered after metformin, a rise was noted in response to meals (from 1.4 +/- 0.1 to 1.8 +/- 0.2 mmol l-1, p less than 0.05). Adipocyte insulin receptor binding was unaffected by drug treatment. Moreover, no insulin-like effects or post-binding potentiation of insulin action could be found on adipocyte glucose transport, glucose oxidation, lipogenesis, glycolysis or antilipolysis. A complementary in vitro study using adipocytes from non-obese healthy volunteers failed to show any direct effect of metformin on adipocyte insulin binding or glucose transport and metabolism, at media drug concentrations corresponding to therapeutic plasma levels.     

Changes in carbohydrate metabolism in association with glipizide treatment of type 2 diabetes

Nineteen patients with Type 2 diabetes were treated with glipizide for 2.5-6 months, and measurements made of metabolic variables before and after glipizide treatment. For purposes of analysis, the glipizide associated decrease in fasting plasma glucose concentration was used to divide patients into 'good' responders (decrease of 4.0 mmol l-1 or more, n = 9) or 'fair' responders (decrease of 3.0 mmol l-1 or less, n = 10). Good responders had a significantly greater fall in their mean (+/- SE) hourly plasma glucose (6.3 +/- 0.6 vs 2.7 +/- 0.3 mmol l-1, p less than 0.001) and NEFA (164 +/- 40 vs 60 +/- 37 mumol l-1, p less than 0.05) concentrations from 0800 to 1600 h in response to meals (0800 and 1200 h) than did the fair responders. However, the increase in hourly plasma insulin concentration following glipizide treatment was the same in the good (323 +/- 103 to 413 +/- 124 pmol l-1) and fair (276 +/- 42 to 345 +/- 43 pmol l-1) responders.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin insensitivity in offspring of parents with type 2 diabetes mellitus

Measurements were made of the plasma glucose and insulin responses to a 75 g oral glucose challenge in 50 Chinese born in Taiwan, divided into two groups on the basis of family history of Type 2 diabetes. Twenty-five individuals (age 29 +/- 5 (+/- SD) years) had 2 parents with normal oral glucose tolerance, whereas at least 1 parent had Type 2 diabetes in the other 25 subjects (age 30 +/- 6 years). In addition, in vivo insulin action was estimated by determining the steady-state plasma glucose concentration during a 3-h continuous infusion of glucose, insulin, and somatostatin. Steady-state plasma glucose concentration was used as a measure of insulin-induced glucose disposal. The 50 subjects were non-obese, and of comparable gender distribution and body mass index. Plasma glucose and insulin concentrations in response to oral glucose were similar in the two groups. However, the steady-state plasma glucose concentration was significantly (p less than 0.01) higher in offspring with a family history of Type 2 diabetes when compared by two-way analysis of variance (mean +/- SE was 5.87 +/- 0.27 vs 5.12 +/- 0.32 mmol l-1). This difference was found despite a significantly (p less than 0.01) higher steady-state plasma insulin concentration during the infusion studies (0.705 +/- 0.027 vs 0.643 +/- 0.025 nmol l-1) in offspring of people with diabetes. The results support the view that resistance to insulin-stimulated glucose uptake is present in offspring of diabetic parents.     

Insulin-induced hypoglycaemia and absorption of injected insulin in diabetic patients

The effect of insulin-induced hypoglycaemia (soluble insulin 1 mU kg-1 min-1 IV) on the absorption of 125I-labelled soluble insulin (10 U SC) from thigh was studied in 10 insulin-treated Type 1 diabetic patients on a test and a control day. Disappearance of 125I was followed by external gamma counting. Adipose tissue blood flow was measured concomitantly using the 133Xe-clearance technique. Arterial plasma levels of glucose, insulin, adrenaline and noradrenaline were determined intermittently. Hypoglycaemia occurred at a glucose level of 2.2 +/- 0.1 (+/- SE) mmol l-1 after 58 +/- 6 min. Peak levels of adrenaline (6.44 +/- 1.62 nmol l-1) and noradrenaline (2.29 +/- 0.39 nmol l-1) were found 10 min later. During the 30-min period after onset of hypoglycaemia, adipose tissue blood flow increased 132 +/- 45% (p less than 0.05) but the disappearance rate of 125I-insulin was unchanged. Thus, insulin absorption was unaltered in connection with hypoglycaemia in Type 1 diabetic patients, in contrast to the depression previously reported in healthy subjects, despite similar increases in adipose tissue blood flow.     

Suppression of insulin secretion by falling plasma glucose levels is impaired in type 2 diabetes

The ability of Type 2 diabetic patients to suppress islet B-cell secretion in response to falling plasma glucose levels has been studied with two different protocols. (1) Five diet-treated diabetic patients and 6 normal subjects were studied after the termination of a hyperglycaemic clamp at 15 mmol l-1 for 150 min, with the plasma glucose levels then being allowed to fall and the glucose clamp re-established at 10 mmol l-1. The plasma insulin levels fell in normal subjects from 178 +/- 141 (+/- SD) mU l-1 at the end of the 15 mmol l-1 clamp to 147 +/- 97 mU l-1 (p less than 0.02) 20 min later, whereas in diabetic patients there was no significant change from 61 +/- 41 to 56 +/- 35 mU l-1, respectively (NS). (2) The second study was performed to assess the turn-off of islet B-cell secretion with diabetic patients and normal subjects starting at comparable plasma insulin levels. Twelve diet-treated diabetic patients and 11 normal subjects were given a continuous low-dose glucose infusion for 60 min at a rate of 5 mg kg-1 ideal body weight min-1, after which the infusion was turned off and the plasma glucose level allowed to fall.(ABSTRACT TRUNCATED AT 250 WORDS)     

A randomized crossover study of sulphonylurea and insulin treatment in patients with type 2 diabetes poorly controlled on dietary therapy

In 13 non-obese patients with Type 2 diabetes mellitus who failed to achieve adequate blood glucose control on dietary treatment (fasting blood glucose 13.4 +/- 2.7 (+/- SD) mmol l-1, glycosylated haemoglobin 13.0 +/- 1.7%), the effects of 6 months insulin or sulphonylurea therapy on blood glucose control and lipid metabolism were compared in a randomized crossover study. Three patients, who showed a clear improvement on insulin (median glycosylated haemoglobin fell from 14.7 to 8.6%), withdrew from the study prematurely because of subjective and objective signs of hyperglycaemia after crossover from insulin to sulphonylurea. Daily dose after 6 months was 2000 mg tolbutamide (n = 3), 18 +/- 1 mg glibenclamide (n = 7), or 34 +/- 3 U insulin. On insulin, fasting (8.0 +/- 1.9 mmol l-1) and postprandial blood glucose (10.4 +/- 2.7 mmol l-1), and glycosylated haemoglobin (9.5 +/- 1.1%) were lower than on sulphonylurea (11.0 +/- 3.4 mmol l-1, 14.4 +/- 4.8 mmol l-1 and 11.0 +/- 2.5%, respectively, p less than 0.05 in each case). Median increase in body weight was greater on insulin (4.2 vs 1.1 kg, p less than 0.05). Six patients experienced improved well-being on insulin compared with sulphonylurea. Median plasma non-esterified fatty acids decreased from 825 mumol l-1 to 476 mumol l-1 (sulphonylurea) and 642 mumol l-1 (insulin, both p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intensive dietary treatment on insulin-stimulated skeletal muscle glycogen synthase activation and insulin secretion in newly presenting type 2 diabetic patients

Ten newly presenting, untreated, Europid Type 2 diabetic patients were studied before and after 8 weeks treatment with intensive diet alone. Nine normal control subjects were also studied. The degree of activation of skeletal muscle glycogen synthase (GS) was used as an intracellular marker of insulin action, prior to and during a 240-min insulin infusion (100 mU kg-1 h-1). Fasting blood glucose decreased from 12.1 +/- 0.9 (+/- SE) to 9.2 +/- 0.8 mmol l-1 (p less than 0.01), but there was no change in fasting insulin concentrations, 9.9 +/- 2.3 vs 9.3 +/- 2.1 mU l-1. Fractional GS activity did not increase in the Type 2 diabetic patients during the insulin infusion either at presentation (change -1.5 +/- 1.9%) or after treatment (change +0.9 +/- 1.8%), and was markedly decreased compared with the control subjects (change +14.5 +/- 2.8%, both p less than 0.001). Glucose requirement during the clamp was decreased in the Type 2 diabetic patients at presentation (2.2 +/- 0.7 vs 7.3 +/- 0.6 mg kg-1 min-1, p less than 0.001), and despite improvement following dietary treatment to 3.3 +/- 0.6 mg kg-1 min-1 (p less than 0.01) remained lower than in the control subjects (p less than 0.001). Fasting plasma non-esterified fatty acid (NEFA) concentrations were elevated at presentation (p less than 0.05), and failed to suppress normally during the insulin infusion. After treatment fasting NEFA concentrations decreased (p less than 0.05) and suppressed normally (p less than 0.05). Insulin secretion was assessed following an intravenous bolus of glucose (0.5 g kg-1) at euglycaemia before and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Islet function and insulin sensitivity in the non-diabetic offspring of conjugal type 2 diabetic patients

To determine whether the genetic predisposition towards Type 2 diabetes was associated with a defect in either islet-cell function or insulin action, 12 non-diabetic offspring each of whose parents both had Type 2 diabetes were studied, together with 12 control subjects matched for age, sex, and weight. Fasting plasma glucose was higher in the offspring (5.5 +/- 0.1 mmol l-1 (mean +/- SE)) than in the matched controls (5.1 +/- 0.1 mmol l-1) (p less than 0.05). Using an IVGTT insulin sensitivity was not significantly lower in the offspring compared with their controls (3.1 +/- 0.5 vs 3.8 +/- 1.0 min-1 mU-1 l 10(-4)). There was no significant difference in any of the measures of insulin secretion (first- and second-phase response to IV glucose, slope of glucose potentiation, and maximal glucose regulated insulin secretory capacity). Glucagon secretion measured before and after a stimulus of IV arginine at varying plasma glucose concentrations was virtually identical in the offspring and their controls. Among a total of 28 non-diabetic subjects of differing body-weights there was a significant inverse relationship between insulin sensitivity and insulin secretion. When adjusted for their generally lower insulin sensitivity, maximal insulin secretory capacity was reduced in the offspring (p = 0.038, one-tailed t-test). The results suggest that the genetic predisposition to Type 2 diabetes is not associated in young adults with any major pre-morbid impairment in insulin secretion or insulin action but the relationship between the two may be abnormal. Islet A-cell function appears to be normal.     

Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes

To investigate the effect of a sustained (7-d) decrease in plasma free fatty acid (FFA) concentration in individuals genetically predisposed to develop type 2 diabetes mellitus (T2DM), we studied the effect of acipimox, a potent inhibitor of lipolysis, on insulin action and adipocytokine concentrations in eight normal glucose-tolerant subjects (aged 40 +/- 4 yr, body mass index 26.5 +/- 0.8 kg/m(2)) with at least two first-degree relatives with T2DM. Subjects received an oral glucose tolerance test (OGTT) and 120 min euglycemic insulin clamp (80 mU/m(2).min) with 3-[(3)H] glucose to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and endogenous (primarily hepatic) glucose production (EGP) before and after acipimox, 250 mg every 6 h for 7 d. Acipimox significantly reduced fasting plasma FFA (515 +/- 64 to 285 +/- 58 microm, P < 0.05) and mean plasma FFA during the OGTT (263 +/- 32 to 151 +/- 25 microm, P < 0.05); insulin-mediated suppression of plasma FFA concentration during the insulin clamp also was enhanced (162 +/- 18 to 120 +/- 15 microm, P < 0.10). Following acipimox, fasting plasma glucose (5.1 +/- 0.1 vs. 5.2 +/- 0.1 mm) did not change, whereas mean plasma glucose during the OGTT decreased (7.6 +/- 0.5 to 6.9 +/- 0.5 mm, P < 0.01) without change in mean plasma insulin concentration (402 +/- 90 to 444 +/- 102 pmol/liter). After acipimox Rd increased from 5.6 +/- 0.5 to 6.8 +/- 0.5 mg/kg.min (P < 0.01) due to an increase in insulin-stimulated nonoxidative glucose disposal (2.5 +/- 0.4 to 3.5 +/- 0.4 mg/kg.min, P < 0.05). The increment in Rd correlated closely with the decrement in fasting plasma FFA concentration (r = -0.80, P < 0.02). Basal EGP did not change after acipimox (1.9 +/- 0.1 vs. 2.0 +/- 0.1 mg/kg.min), but insulin-mediated suppression of EGP improved (0.22 +/- 0.09 to 0.01 +/- 0.01 mg/kg.min, P < 0.05). EGP during the insulin clamp correlated positively with the fasting plasma FFA concentration (r = 0.49, P = 0.06) and the mean plasma FFA concentration during the insulin clamp (r = 0.52, P < 0.05). Plasma adiponectin (7.1 +/- 1.0 to 7.2 +/- 1.1 microg/ml), resistin (4.0 +/- 0.3 to 3.8 +/- 0.3 ng/ml), IL-6 (1.4 +/- 0.3 to 1.6 +/- 0.4 pg/ml), and TNFalpha (2.3 +/- 0.3 to 2.4 +/- 0.3 pg/ml) did not change after acipimox treatment.We concluded that sustained reduction in plasma FFA concentration in subjects with a strong family history of T2DM increases peripheral (muscle) and hepatic insulin sensitivity without increasing adiponectin levels or altering the secretion of other adipocytokines by the adipocyte. These results suggest that lipotoxicity already is well established in individuals who are genetically predisposed to develop T2DM and that drugs that cause a sustained reduction in the elevated plasma FFA concentration may represent an effective modality for the prevention of T2DM in high-risk, genetically predisposed, normal glucose-tolerant individuals despite the lack of an effect on adipocytokine concentrations.     

A double blind study of the effect of acipimox on serum lipids, blood glucose control and insulin action in non-obese patients with type 2 diabetes mellitus.

Hyperlipidaemia, in particular raised concentrations of serum triglycerides, together with raised plasma non-esterified fatty acid concentrations, is common in patients with Type 2 (non-insulin-dependent) diabetes mellitus and may be associated with insulin insensitivity. Thirty non-obese Type 2 diabetic patients (15 controlled with diet alone and 15 with diet plus oral sulphonylurea therapy) were therefore recruited to take part in a double-blind, randomized, crossover comparison of acipimox (250 mg three times daily for 3 months) and placebo. Serum lipids, blood glucose control, insulin sensitivity, and glucose tolerance were measured before and after each treatment period. There was a significant decrease in serum triglycerides (2.05 +/- 1.08 vs 2.91 +/- 1.75: p < 0.005), cholesterol (5.66 +/- 1.02 vs 6.26 +/- 1.17: p = 0.0005), and apoprotein B (1.32 +/- 0.23 vs 1.44 +/- 0.25: p < 0.05) while HDL cholesterol and apoprotein A-1 concentrations were unchanged. There was no change in blood glucose control measured by fasting glucose, insulin, and HBA, concentrations, but there was a significant improvement in insulin action assessed by glucose-insulin infusion. Although plasma non-esterified fatty acid concentrations were lower during the oral glucose tolerance test after acipimox, there was no difference in either the peak or 2-h plasma glucose concentrations and the total area under the glucose curve did not change. Acipimox was well tolerated and no patients withdrew from the study for drug-related symptoms. Thus, acipimox effectively lowers serum cholesterol and triglycerides in patients with Type 2 diabetes without adversely altering blood glucose control, and appears to improve insulin sensitivity.     

Morning versus bedtime isophane insulin in type 2 (non-insulin dependent) diabetes mellitus.

Morning versus bedtime administration of NPH insulin was compared in 12 subjects with Type 2 diabetes and overt fasting hyperglycaemia. Subjects were studied at baseline (diet alone) and after 2 months on each of the two insulin programmes in a random crossover design, in which dosage was increased until at least one daily preprandial blood glucose was consistently in the range of 3.9 to 6.0 mmol l-1. Mean (+/- SEM) daily total insulin dosage was equivalent for the morning (0.36 +/- 0.03 units kg-1) and for the bedtime (0.37 +/- 0.03 units kg-1) insulin administration schedules. Glycaemic control was improved on both insulin regimens, but was better on bedtime than morning insulin. Fasting plasma glucose (mmol l-1) was 12.0 +/- 0.7 (baseline), 8.6 +/- 0.7 (morning), and 4.6 +/- 0.3 (bedtime), respectively. Mean 24 h plasma glucose (mmol l-1) was 13.3 +/- 1.3, 9.0 +/- 0.7, and 7.8 +/- 0.7. Glycated haemoglobin (%) was 7.65 +/- 0.35, 6.23 +/- 0.26, and 5.81 +/- 0.32. The improvement of basal glycaemia is a consequence of increased basal metabolic clearance of glucose (baseline, 47.6 +/- 3.1 ml m-2 min-1; morning 63.5 +/- 5.4, bedtime 103.5 +/- 7.1). There was no change in hepatic glucose output. It is concluded that bedtime administration of intermediate acting insulin results in increased basal insulinaemia, leading to improved basal glycaemia and consequent improved overall metabolic control, compared to morning insulin administration. Therefore, bedtime may be the preferable timing of insulin therapy for patients with Type 2 diabetes and overt fasting hyperglycaemia.     

Insulin antibodies do not influence the absorption rate of subcutaneously injected insulin

The influence of insulin antibodies on absorption rate and plasma free insulin concentrations after subcutaneous injection of insulin, was studied in two groups of insulin-treated diabetic patients, one without insulin antibodies (n = 9) and a second with high plasma concentrations of antibodies (n = 14). Except for antibody concentration there were no differences in clinical variables. During 8 h after the injection of 12 U of iodinated neutral human insulin, residual radioactivity at the injection site, plasma glucose, and free and total insulin were measured. Significant differences in absorption rate of insulin were not found between the groups. Plasma glucose (basal value 16.8 +/- 4.4 SD vs 16.1 +/- 4.2 mmol l-1) and free insulin (basal value 8.3 +/- 1.4 vs 11.4 +/- 2.3 mU l-1, maximum after 90 min 36.9 +/- 19.5 vs 30.5 +/- 18.7 mU l-1) were never significantly different between the groups, nor were areas under the curve for free insulin (191.4 +/- 69.2 vs 170.8 +/- 98.6 mU l-1 h). In the high antibody group a small increase in bound insulin was found.     

Pulsatile insulin infusion and glucose-homeostasis in well-controlled type 1 (insulin-dependent) diabetic patients

Pulsatile, intravenous insulin infusion designed to mimic the portal insulin concentrations that emerge physiologically after a meal, has been postulated to improve glucose tolerance in Type 1 (insulin-dependent) diabetic patients. We studied the effects of insulin pulsing (10 i.v. pulses of human insulin of 0.035 U kg-1 idealised body weight were given, each of 20 s duration, with intervals of 6 min, three times per day covered with adequate administration of glucose) on 2 successive days on glucose-tolerance in nine well-controlled Type 1 diabetic patients on continuous subcutaneous insulin infusion therapy (age 26 (7) years, mean (SD); duration of diabetes 10 (7) years; body mass index 23.4 (2.3) kg m-2; HbA1c 6.0 (0.6)%). On the days before and after the insulin pulsing, the patients were subjected to metabolic assessments by an oral glucose tolerance test (1 g glucose kg-1 body weight) 30 min after the subcutaneous injection of 0.15 U kg-1 body weight regular human insulin and a subsequent bicycle-ergometer test. During these metabolic assessments, plasma free insulin concentrations, plasma glucagon and the non-protein respiratory quotient remained unaffected by the insulin pulsing. However, glucose tolerance deteriorated significantly (maximal glucose concentration 120 min after glucose load was 10.0 mmol l-1 before and 13.9 mmol l-1 after insulin pulsing, P less than 0.01). In conclusion, the pattern of insulin pulsing used in this study did not ameliorate oral glucose homeostasis in well-controlled Type 1 (insulin dependent) diabetic patients.