Troglitazone,an insulin action enhancer,improves glycaemic control and insulin sensitivity in elderly Type 2 diabetic patients

The management of Type 2 diabetes mellitus with currently available oral agents may be complicated in the elderly by an increased frequency of side-effects. The effects of troglitazone, an insulin action enhancer, were studied in elderly patients with Type 2 diabetes in a double-blind, parallel-group, placebo-controlled trial. A total of 229 patients (41 % male), mean age 75 (range 69–85) years, with two fasting capillary blood glucose values ≥7 and ≤15 mmol l⁻¹ (and within 4.0 mmol l⁻¹ of each other) and previously treated with either diet alone (30 %) or oral hypoglycaemic agents, were randomized to placebo or troglitazone 400 mg once daily or 200 mg twice daily, or 800 mg once daily or 400 mg twice daily, for 12 weeks. After 12 weeks’ treatment, fasting serum glucose was significantly lower in troglitazone-treated patients (troglitazone, adjusted geometric mean 9.4–10.4 mmol l⁻¹ vs placebo 12.7 mmol l⁻¹, p<0.001). Adjusted geometric mean fructosamine was also lower in troglitazone-treated patients by 5 to 15 % compared to placebo (P <0.05 at all doses except 400 mg od). There was no significant difference between troglitazone doses for improvement in glycaemic control. Troglitazone lowered adjusted geometric mean fasting plasma insulin by 27–34 % compared to placebo (P<0.001) and insulin sensitivity (HOMA-S) improved by 9–15 % in all troglitazone dose groups (p<0.001). Troglitazone also lowered serum non-esterified fatty acids and triglyceride. Adverse event incidence in troglitazone-treated patients was similar to that in patients treated with placebo. No weight gain or symptomatic hypoglycaemia was recorded at any of the doses studied. Troglitazone is effective and well tolerated in elderly patients with Type 2 diabetes mellitus, providing improved glycaemic control in the absence of weight gain. © 1998 John Wiley & Sons, Ltd.     

Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in Type 2 diabetic patients

Intravenous GLP-1 [7-36 amide] can normalize fasting hyperglycaemia in Type 2 diabetic patients. Whether GLP-1 [7-37] has similar effects and how quickly plasma glucose concentrations revert to hyperglycaemia after stopping GLP-1 is not known. Therefore, 8 patients with Type 2 diabetes (5 female, 3 male; 65 ± 6 years; BMI 34.3 ± 7.9 kg m⁻²; HbA_1c 9.6 ± 1.2 %; treatment with diet alone (n = 2), sulphonylurea (n = 5), metformin (n = 1)) were examined twice in randomized order. GLP-1 [7-36 amide] or [7-37] (1 pmol kg⁻¹min⁻¹) were infused intravenously over 4 h in fasted subjects. Plasma glucose (glucose-oxidase), insulin and C-peptide (ELISA) was measured during infusion and for 4 h thereafter. Indirect calorimetry was performed. Fasting hyperglycaemia was 11.7 ± 0.9 [7-36 amide] and 11.3 ± 0.9 mmol l⁻¹ [7-37]. GLP-1 infusions stimulated insulin secretion approximately 3-fold (insulin peak 168 ± 32 and 156 ± 47 pmol l⁻¹, p < 0.0001 vs basal; C-peptide peak 2.32 ± 0.28 and 2.34 ± 0.43 nmol l⁻¹, p < 0.0001, respectively, with GLP-1 [7-36 amide] and [7-37]). Four hours of GLP-1 infusion reduced plasma glucose (4.8 ± 0.4 and 4.6 ± 0.3 mmol l⁻¹, p < 0.0001 vs basal values), and it remained in the non-diabetic fasting range after a further 4 h (5.1 ± 0.4 and 5.3 ± 0.4 mmol l⁻¹, for GLP [7-36 amide] and [7-37], respectively). There were no significant differences between GLP-1 [7-36 amide] and [7-37] (glucose, p = 0.99; insulin, p = 0.99; C-peptide, p = 0.99). Neither glucose oxidation nor lipid oxidation (or any other parameters determined by indirect calorimetry) changed during or after the administration of exogenous GLP-1. In conclusion, GLP-1 [7-36 amide] and [7-37] normalize fasting hyperglycaemia in Type 2 diabetic patients. Diabetes therapy (diet, sulphonyl ureas or metformin) does not appear to influence this effect. In fasting and resting patients, the effect persists during administration of GLP-1 and for at least 4 h thereafter, without rebound. Significant changes in circulating substrate concentrations (e.g. glucose) are not accompanied by changes in intracellular substrate metabolism. © 1998 John Wiley & Sons, Ltd.     

Prandial Glycaemia After a Carbohydrate-rich Meal in Type I Diabetic Patients: Using the Rapid Acting Insulin Analogue [Lys(B28), Pro(B29)] Human Insulin

The time–action profile of the insulin analogue insulin lispro ([Lys(B28), Pro(B29)] human insulin) with its rapid onset and short duration of action might be more suitable to limit hyperglycaemic excursions after a meal rich in rapidly absorbable carbohydrates in comparison to regular human insulin. A randomized, double-blind study was performed in 10 Type I diabetic patients with good metabolic control (HbA_1c 7.0 ± 0.5 %). After a baseline period of 3 h (blood glucose clamped at 6.7 mmol l⁻¹, i.v. insulin infusion of 0.2 mU kg⁻¹ min⁻¹ throughout the study), the patients ate a pizza, drank a cola and had a carbohydrate-rich dessert (total carbohydrate content 140 g). Immediately before the meal 15.4 ± 3.5 U of either insulin preparation were injected subcutaneously. Blood glucose concentrations were monitored continuously thereafter. Following the injection of insulin lispro the area under the blood glucose curve after the meal was 78 % of that of regular insulin (1.76 ± 0.34 vs 2.26 ± 0.68 mol l⁻¹ *240 min⁻¹; p < 0.01). Maximal blood glucose excursions were higher and were reached later after regular insulin as compared to insulin lispro (11.9 ± 2.8 vs 9.9 ± 1.4 mmol l⁻¹; p < 0.05; 66 ± 37 vs 41 ± 7 min; p < 0.05). Maximal individual differences in the blood glucose excursions (regular human insulin minus insulin lispro) were 4.8 ± 2.2 mmol l⁻¹ (p < 0.0001 against zero) after 110 ± 37 min. In Type I diabetic patients prandial blood glucose excursions after a carbohydrate rich meal were reduced after preprandial injection of insulin lispro in comparison to human regular insulin.     

Fructose and insulin sensitivity in patients with type 2 diabetes

Abstract. The effect of dietary fructose (20% of carbohydrate calories, 45–65 g day^?1 for 4 weeks) on glycaemic control, serum lipid, lipoprotein and apoprotein A-I and A-II concentrations and on insulin sensitivity was studied in 10 type 2 diabetic patients. The study was done in a randomized, double-blind fashion with crystalline fructose or placebo administered evenly during 4 meals or snacks per day. The patients were hospitalized throughout the study periods. The fasting plasma glucose concentration decreased during the fructose (from 10.7 ± 1.4 mmol l^?1 to 8.0 ± 0.8 mmol l^?1, P < 0.02) and the control diet (from 10.1 ± 0.9 mmol l^?1 to 8.0 ± 0.7 mmol l^?1 P < 0.05). The mean diurnal blood glucose concentration also fell both during the fructose (from 10.8± 0.5 mmol l^?1 to 8.4 ± 0.3 mmol l^?1, P < 0.001) and the control diet (from 10.3 ± 0.3 mmol l^?1 to 8.8 ± 0.9 mmol l^?1, P < 0.01). The HbA₁ concentration improved (P < 0.02) only during the fructose diet. Insulin sensitivity increased by 34% (P < 0.05) during the fructose diet, but remained unchanged during the control period. Serum insulin, triglyceride, apoprotein A-I and A-II concentrations, body weight, blood pressure and blood lactate remained unchanged during both diets. In conclusion, substitution of moderate amounts of fructose for complex carbohydrates can improve glycaemic control and insulin sensitivity in patients with type 2 diabetes.     

Counterregulatory Hormone Responses and Symptoms During Hypoglycaemia Induced by Porcine,Human Regular Insulin,and Lys(B28), Pro(B29) Human Insulin Analogue (Insulin Lispro) in Healthy Male Volunteers

Lys(B28)Pro(B29) human insulin analogue (Lispro) is a newly developed monomeric insulin analogue with a rapid onset and short duration of action. The aim of the study was to compare the thresholds for the counterregulatory responses during a stepwise euglycaemic/hypoglycaemic clamp for insulin lispro (LP), human (H), and porcine (P) insulin in a randomized order in 12 healthy male volunteers (age 22.4 ± 1.7 years, BMI 21.9 ± 1.7 kg m⁻²). A euglycaemic period of 2 h was followed by three hypoglycaemic levels of 60 min each: from 150–210 min at 3.5 mmol l⁻¹, 240–300 min at 3.0 mmol l⁻¹, and 330–390 min at 2.5 mmol l⁻¹. Plasma insulin levels during the 50 mU kg⁻¹ h⁻¹ infusions and blood glucose levels were not significantly different. The glucose requirements (mean ± SD) during the last part of the euglycaemic period (90–120 min) tended to be higher during LP compared to those during H and P; 2239 ± 702 and 1929 ± 769, 1957 ± 725 mg kg⁻¹, P = 0.067, respectively. The thresholds (blood glucose level at which a sustained elevation of the counterregulatory hormones as compared to the mean at normoglycaemia level 4.0 mmol l⁻¹ , occurs) for the various hormones were very similar during LP, H, and P insulin infusions and occurred at 253.8 ± 56.7, 256.3 ± 55.3 and 257.5 ± 70.0 min for adrenaline; 241.4 ± 80.3, 260.5 ± 82.5 and 225.0 ± 75.9 min for noradrenaline; 307.5 ± 65.5, 304.1 ± 74.1 and 322.5 ± 40.4 min for cortisol; 263.8 ± 50.3, 255.0 ± 63.6 and 249.6 ± 50.9 min for growth hormone; 236.3 ± 78.2, 200.0 ± 73.1 and 226.3 ± 65.5 for pancreatic polypeptide. The autonomic and neuroglycopenic symptoms were elicited at 240 and 300 min, respectively. In conclusion, our data indicate a tendency to a higher biological activity of approximately 10 % for Lispro insulin. During a stepwise euglycaemic/hypoglycaemic clamp, the counterregulatory hormone responses to insulin lispro, human insulin, and porcine insulin were similar. © 1997 by John Wiley & Sons, Ltd.     

Adding metformin versus insulin dose increase in insulin-treated but poorly controlled Type 2 diabetes mellitus: an open-label randomized trial

To compare the effect of adding metformin to insulin therapy with a moderate increase in insulin dose alone in insulin-treated, poorly controlled Type 2 diabetic patients, 47 consecutive such patients (baseline daily dose >0.5 IU kg⁻¹ and HbA_1c >8 %) were openly randomized either to a combination of their previous insulin schedule plus metformin (2.55 g daily in three divided doses, n = 24) or to a moderate insulin dose increase (20 % of baseline, n = 23). The patient status/biochemical profile was assessed at entry and at 4 months. Among those assigned to insulin + metformin, 18 took the drug. Upon an intention-to-treat basis, patients assigned to insulin dose increase had a statistically significant weight gain (1.16 + 1.9 vs 0.3 ± 4.5 kg, p < 0.05). Patients assigned to the insulin + metformin regimen experienced a significantly greater fall in HbA_1c (−1.87 ± 2.16 vs 0.03 ± 1.68 %, p < 0.01), total cholesterol (−0.56 ± 0.89 vs 0.14 ± 0.72 mmol l⁻¹, p < 0.05) and LDL-cholesterol (−0.51 ± 0.73 vs 0.19 ± 0.6 mmol l⁻¹, p < 0.01). These data suggest that adding metformin to insulin in poorly controlled Type 2 DM patients offers an advantage in terms of glycaemic control and lipid plasma profile. Copyright © 1998 John Wiley & Sons, Ltd.     

Spontaneous hypoglycaemia after pancreas transplantation in Type 1 diabetes mellitus

Hypoglycaemia is an important complication of insulin treatment in Type 1 diabetes mellitus (DM). Pancreas transplantation couples glucose sensing and insulin secretion, attaining a distinctive advantage over insulin treatment. We tested whether successful transplantation can avoid hypoglycaemia in Type 1 DM. Combined kidney and pancreas transplanted Type 1 DM who complied with good function criteria (KP-Tx, n = 55), and isolated kidney or liver transplanted non-diabetic subjects on the same immunosuppressive regimen (CON-Tx, n = 14), underwent 1-day metabolic profiles in the first 3 years after transplantation, sampling plasma glucose (PG) and pancreatic hormones every 2 hours. KP-Tx had lower PG than CON-Tx in the night and in the morning and higher insulin concentrations throughout the day. KP-Tx had lower PG nadirs than CON-Tx (4.40 ± 0.05 vs 4.96 ± 0.16 mmol l⁻¹, ANOVA p = 0.001). Nine per cent of KP-Tx had hypoglycaemic values (PG ≤3.0 mmol l⁻¹) in the profiles, both postprandial and postabsorptive, whereas none of CON-Tx did (p < 0.02). In conclusion, after pancreas transplantation, mild hypoglycaemia is frequent, although its clinical impact is limited. Compared to insulin treatment in Type 1 DM, pancreas transplantation improves but cannot eliminate hypoglycaemia. Copyright © 1998 John Wiley & Sons, Ltd.     

Reducing snacks when switching from conventional soluble to lispro insulin treatment: effects on glycaemic control and hypoglycaemia

The lack of significant improvement in HbA_1c during insulin lispro treatment in previous studies may have been due to inadequate dietary adjustments. We tested whether reduction of snacks and a compensatory increase in main meals results in improved metabolic control when switching to lispro treatment. One hundred and forty-one Type 1 diabetic patients, mean ± SD age 36 ± 9 years, diabetes duration 14 ± 10 years, had two daily NPH injections throughout the study. After a baseline visit, the patients used conventional soluble insulin preprandially thrice daily for 12 weeks. Thereafter they were switched to lispro insulin and advised to transfer ≥50 % of their snack carbohydrates to preceding main meals. Mean HbA_1c at baseline was 8.05 %. After the conventional period and the 12-week lispro period, HbA_1c was 7.81 and 7.70 % (p = 0.088), respectively. In those patients who diminished their snacks as advised (n = 67), HbA_1c decreased from 7.91 to 7.66 % (p = 0.014) during lispro, whereas no change was observed in patients not compliant with the dietary change. The number of hypoglycaemic episodes was lower during lispro period (blood glucose <2.5 mmol l⁻¹: 1.43 vs 2.19 episodes, p = 0.004; symptomatic nocturnal hypoglycaemia 1.16 vs 1.67 episodes, p<0.001). When switching from conventional soluble to lispro insulin, reduction of snack carbohydrates is safe and results in slightly improved HbA_1c in patients who are fully compliant with the dietary change. © 1998 John Wiley & Sons, Ltd.     

Insulin resistant subjects lack islet adaptation to short-term dexamethasone-induced reduction in insulin sensitivity

Aims/hypothesis. To establish whether islet compensation to deterioration of insulin action depends on inherent insulin sensitivity. Methods. We examined insulin and glucagon secretion after iv arginine (5 g) at fasting, 14 and greater than 25 mmol/l glucose concentrations before and after lowering of insulin sensitivity by oral dexamethasone (3 mg twice daily for 2 1/2 days) in 10 women with normal glucose tolerance, aged 58 or 59 years. Five women had high insulin sensitivity as shown by euglycaemic, hyperinsulinaemic clamp (99 ± 12 nmol glucose · kg body weight^–1· min^–1/pmol insulin · l^–1; means ± SD) whereas five women had low insulin sensitivity (34 ± 15 nmol glucose · kg body weight^–1· min^–1/pmol insulin · l^–1). Results. Dexamethasone reduced insulin sensitivity in both groups. Fasting insulin concentration increased by dexamethasone in high insulin sensitivity (72 ± 10 vs 49 ± 9 pmol/l, p = 0.043) but not in low insulin sensitivity (148 ± 63 vs 145 ± 78 pmol/l) whereas the fasting glucose concentration increased in low insulin sensitivity (6.5 ± 0.8 vs 5.8 ± 0.6 mmol/l, p = 0.043) but not in high insulin sensitivity (5.3 ± 0.8 vs 5.3 ± 0.6 mmol/l). Fasting glucagon concentration was not changed. Plasma insulin concentrations after raising glucose to 14 and more than 25 mmol/l and the insulin response to arginine at more than 25 mmol/l glucose were increased by dexamethasone in high insulin sensitivity (p < 0.05) but not changed by dexamethasone in low insulin sensitivity. Furthermore, in high but not in low insulin sensitivity, dexamethasone reduced the glucagon response to arginine (p = 0.043). Conclusion/interpretation. The results show that adaptation in islets function to dexamethasone-induced short-term reduction in insulin sensitivity is lacking in subjects with low inherent insulin sensitivity. [Diabetologia (1999) 42: 936–943] Received: 26 January 1999 and in revised form: 1 March 1999     

Human insulin analogue [LYS(B28), PRO(B29)]: the ideal pump insulin?

The short-acting insulin analogue lispro [LYS(B28), PRO(B29)] is absorbed from the subcutis more rapidly than soluble insulin (S). To compare the clinical effectiveness of lispro vs S, 11 Type 1 patients using continuous subcutaneous insulin infusion (CSII) therapy (6 F, 5 M, age 30 ± 2.5 years, diabetes duration 14 ± 1.0 years, BMI 24.0 ± 0.8 kg m⁻², HbA_1c 6.5 ± 0.2 %) were studied in an open, randomized, crossover study for 6 months (3 months lispro and 3 months S or vice versa). During lispro treatment mean fasting and 2 h postprandial blood glucose were lower compared to the S phase (fasting 6.5 ± 0.4 vs 7.5 ± 0.4 mmol l⁻¹ (NS), postprandial 6.8 ± 0.3 vs 8.3 ± 0.3 mmol l⁻¹, p = 0.03). In patients treated first with lispro HbA_1c levels improved from 6.3 ± 0.2 % to 5.7 ± 0.3 %; On reversion to S HbA_1c increased to 6.2 ± 0.2 %. In the group treated first with S, HbA_1c fell (6.7 ± 0.4 % vs 6.5 ± 0.3 %) and then improved further to 6.3 ± 0.3% with lispro. None of these changes were significant. There was no significant difference with respect to hypoglycaemic or other adverse events. It can be concluded that lispro in CSII therapy is safe and may improve postprandial glucose excursions. © 1998 John Wiley & Sons, Ltd.     

Oral magnesium supplementation in insulin-requiring Type 2 diabetic patients

Oral magnesium (Mg) supplementation can improve insulin sensitivity and secretion in patients with Type 2 diabetes mellitus (DM). We studied the effect of Mg supplementation on glycaemic control, blood pressure, and plasma lipids in insulin-requiring patients with Type 2 DM. Fifty moderately controlled patients were randomized to 15 mmol Mg or placebo daily for 3 months. Plasma Mg, glucose, HbA_1c, lipids, erythrocyte Mg, Mg and glucose concentrations in 24-h urine, and systolic and diastolic pressure were measured before and after 3 months treatment. Plasma Mg concentration was higher after supplementation than after placebo (0.82 ± 0.07 vs 0.78 ± 0.08 mmol l⁻¹, p<0.05), as was Mg excretion (5.5 ± 1.9 vs 3.7 ± 1.4 mmol 24 h⁻¹, p = 0.004) but erythrocyte Mg concentrations were similar. No significant differences were found in glycaemic control (glucose: 10.7 ± 3.8 vs 11.6 ± 6.2 mmol l⁻¹, p = 0.8; HbA_1c: 8.9 ± 1.6 vs 9.1 ± 1.2%, p = 0.8), lipids or blood pressure. On-treatment analysis (34 patients: 18 on Mg, 16 on placebo) yielded similar results. An increase in plasma Mg concentration irrespective of medication was associated with a tendency to a decrease in diastolic pressure (increased plasma Mg vs no increase: −4.0 ± 10.1 vs +2.5 ± 12.0 mmHg, p = 0.059). Three months’ oral Mg supplementation of insulin-requiring patients with Type 2 DM increased plasma Mg concentration and urinary Mg excretion but had no effect on glycaemic control or plasma lipid concentrations. © 1998 John Wiley & Sons, Ltd.     

NEFA elevation during a hyperglycaemic clamp enhances insulin secretion

Elevated non-esterified fatty acid (NEFA) levels may influence insulin secretion and contribute to the development of Type 2 DM. We investigated the effects of acute NEFA elevation in controls (n = 6) and subjects predisposed to Type 2 DM (n = 6) on basal insulin levels, and following glucose and arginine stimulation. Each subject had one study with a triglyceride (TG) plus heparin infusion (elevated NEFA levels) and another with normal saline. Twenty minutes after the TG or saline infusion began a glucose bolus was given and 10 min later a 90-min hyperglycaemic clamp (∼ 9 mmol l⁻¹) was started. Intravenous arginine was given at 110 min. Elevated NEFA levels (∼ 4000 μmol l⁻¹) did not enhance basal or first phase glucose stimulated insulin levels. During hyperglycaemia, NEFA elevation further increased insulin levels in both groups by 20–44 % (p < 0.05) and C-peptide levels by 17–25 % (p < 0.05). The post-arginine insulin levels during hyperglycaemia were increased by 45 % in the Type 2 DM-risk group (p < 0.02). The glucose infusion rate maintaining matched hyperglycaemia was similar during NEFA elevation and for saline control for both groups. We conclude that acute elevation of NEFA levels enhances glucose and non-glucose-induced insulin secretion. © 1998 John Wiley & Sons, Ltd.     

Effect of Combination Therapy of Troglitazone and Sulphonylureas in Patients with Type 2 Diabetes Who Were Poorly Controlled by Sulphonylurea Therapy Alone

The clinical efficacy of troglitazone, a new oral hypoglycaemic agent was investigated in Type 2 diabetes in combination with sulphonylureas. Two hundred and ninety-one patients with Type 2 diabetes (age 21–81 years) whose previous glycaemic control by sulphonylureas was judged stable but unsatisfactory (fasting plasma glucose (FPG) > 8.3 mmol l⁻¹) were randomly allocated into the troglitazone treatment group (troglitazone group, n = 145) or the placebo treatment group (placebo group, n = 146). They were treated by test drugs for 12 weeks in combination with the same dose of sulphonylureas before the trial. One hundred and twenty-two patients who received troglitazone and 126 patients who received placebo were evaluated for efficacy. The baseline characteristics did not differ significantly between the two groups. In the troglitazone group, FPG and HbA_1C decreased significantly after the treatment (before vs after, FPG: 10.8 ± 2.0 mmol l⁻¹ vs 9.2 ± 2.5 mmol l⁻¹, p < 0.001; HbA_1C: 9.2 ± 1.4 % vs 8.5 ± 1.5 %, p < 0.001). FPG and HbA_1C did not change after the treatment in the placebo group (before vs after, FPG: 10.5 ± 1.7 mmol l⁻¹ vs 10.7 ± 2.2 mmol l⁻¹; HbA_1C: 9.0 ± 1.5 % vs 9.2 ± 1.6 %). Serum total cholesterol and HDL-cholesterol did not change in either group, however, serum triglyceride significantly decreased in the troglitazone group. No serious adverse events occurred in either group. In conclusion, troglitazone 400 mg day⁻¹ had a significant hypoglycaemic effect in combination with sulphonylureas without any serious adverse events. Troglitazone, developed as an insulin action enhancer, can be a useful hypoglycaemic agent in the treatment of patients with Type 2 diabetes who are not well controlled by sulphonylureas alone.     

No deterioration in insulin sensitivity,but impairment of both pancreatic β-cell function and glucose sensitivity,in Japanese women with former gestational diabetes mellitus

To identify the primary pathogenic factors involved in the development of Type 2 diabetes mellitus (DM), we studied Japanese women with former gestational diabetes mellitus (GDM) who are at risk for the later development of Type 2 DM. We used the minimal model analysis derived from frequently sampled intravenous glucose tolerance test (FSIGT). The subjects consisted of eight non-obese women with a history of GDM and eight non-obese normal women as control subjects. The 75 g oral glucose tolerance test (75 g OGTT) performed within 6 months of delivery confirmed that all the subjects with former GDM had a normal glucose tolerance. Insulin sensitivity (SI) derived from the minimal model analysis was not different between the two groups. Glucose effectiveness at zero insulin (GEZI), reflecting tissue glucose sensitivity, was significantly lower in former GDM patients than in control subjects (1.18 ± 0.34 vs 2.26 ± 0.29 × 10⁻² min⁻¹, p < 0.05). The early phase insulin secretion found in FSIGT was markedly reduced to 56 % of that observed in control subjects (1250 ± 187.4 vs 2223 ± 304.3 pmol l⁻¹ min, p < 0.01). Our results indicate that in former GDM patients, who are Japanese and non-obese, impairment of the acute insulin response to glucose and a decrease in tissue glucose sensitivity rather than insulin sensitivity are the primary pathogenic factors involved. Copyright © 1998 John Wiley & Sons, Ltd.     

High glucose uptake by adipocytes in a Type 1 diabetic patient with a partial ‘honeymoon’ period

Hypoglycaemic episodes and low insulin requirements are frequently seen in the early phase of treatment of Type 1 diabetes mellitus but the mechanism is not clear. We present a diabetic patient with recurrent hypoglycaemia in the early phase of insulin treatment. A very high glucose transport in adipocytes (basal: 176 and insulin stimulated glucose transport 10⁻⁷ mol l⁻¹: 335 fl cell⁻¹ s⁻¹) was found when compared with reference laboratory diabetic patients (basal: 59 ± 10 and insulin 10⁻⁷ mol l⁻¹: 106 ± 7 fl cell⁻¹ s⁻¹, mean ± SE) and with reference laboratory of non-diabetic subjects (basal: 106 ± 6 and insulin 10⁻⁷ mol l⁻¹: 188 ± 15 fl cell⁻¹ s⁻¹). Insulin binding to adipocytes was in the normal range. The patient was studied again 1 year later when the partial clinical remission had disappeared, and the glucose transport in adipocytes had decreased. In conclusion, an increase in glucose uptake by peripheral tissues may be among the mechanisms of the partial ‘honeymoon’ period of diabetic patients. © 1998 John Wiley & Sons, Ltd.     

Metformin and Exercise: no Additive Effect on Blood Lactate Levels in Healthy Volunteers

Metformin administration has been associated with substantial rises in blood lactate concentrations in individual Type 2 diabetic patients. Exercise also leads to increases in blood lactate levels. The objective of this study was to determine whether metformin administration augments the rise in plasma lactate concentrations during intermittent exercise in healthy subjects, when compared to placebo. Twelve healthy males (age 28 ± 5 years, body mass index 22.7 ± 1.3 kg m⁻²) took either 1.7 g metformin or placebo daily for 4 consecutive days before being subjected to strenuous intermittent exercise. On the morning of the fourth day exercise was performed on an upright bicycle ergometer at a work load of 200 W for 2 min alternating with 2 min rest for an overall duration of 60 min. Maximal plasma lactate levels during exercise (metformin: 4.1 ± 2.6 mmol l⁻¹, placebo: 4.5 ± 2.6 mmol l⁻¹), areas under the plasma lactate curve (207 ± 121 vs 222 ± 133 mmol l⁻¹ h⁻¹), blood pyruvate levels at the end of exercise (0.06 ± 0.04 vs 0.07 ± 0.04 mmol l⁻¹), lactate/pyruvate ratio (65 ± 41 vs 60 ± 36), serum insulin (25.4 ± 8.9 vs 32.3 ± 13.0 pmol l⁻¹), and plasma glucose (4.4 ± 0.3 vs 4.5 ± 0.3 mmol l⁻¹) did not differ significantly between metformin and placebo administration. Administration of metformin did not lead to an augmented rise in endogenous plasma lactate concentrations during intermittent exercise in healthy fasting subjects under the experimental design chosen. © 1997 by John Wiley & Sons, Ltd.     

Improved Blood Glucose Control by Insulin Therapy in Type 2 Diabetic Patients Has No Effect on Lipoprotein(a) Levels

The effects of improved blood glucose control by insulin therapy on lipoprotein(a) and other lipoproteins were studied in 54 patients with Type 2 diabetes (mean ± SD: age 67 ± 9 years, body mass index 26.1 ± 4.4 kg m^?2, median duration of diabetes 10 (range 1–37) years, 23 males, 31 females), who were poorly controlled despite diet and maximal doses of oral hypoglycaemic agents. After 6 months of insulin treatment, mean fasting blood glucose concentrations had decreased from 14.1 ± 2.2 mmol l^?1 to 8.4 ± 1.8 mmol l^?1 (p < 0.001), and HbA^1c had fallen from 11.1 ± 1.4 % to 8.2 ± 1.1 % (p < 0.001). Significant decreases of total and LDL cholesterol, triglycerides, apolipoprotein B, and free fatty acids were observed, while HDL-cholesterol and apoA1 increased by 10 %. Baseline serum Lp(a) levels were elevated compared to non-diabetic subjects of similar age (median 283, range 8–3050 mg I^?1, vs 101, range 8–1747 mg I^?1, p < 0.05), but did not change with insulin, and there was no correlation with the degree of metabolic improvement and changes in Lp(a) levels. It is concluded that improved blood glucose control by insulin therapy does not alter elevated Lp(a) levels in Type 2 diabetic patients, but has favourable effects on the other lipoproteins.     

Insulin sensitivity in cardiological syndrome X

Objectives. To test whether cardiological syndrome X is an insulin-resistant state. Setting, design and subjects. The coronary care unit of a referral centre for angina pectoris in Pisa, Italy. A case-control study, involving 10 patients with unequivocal (angiographycally proven) cardiological syndrome X, but normal glucose tolerance, blood pressure and lipid levels, and 13 matched healthy subjects. Main outcome measures. Insulin sensitivity and pattern of substrate oxidation (assessed by the euglycaemic insulin clamp technique in combination with indirect calorimetry). Results. Fasting plasma glucose and insulin levels were 5.05±0.11 versus 4.88±0.11 mmol l^-1 and 68±10 versus 56±6 pmol l^-1, respectively (controls versus patients, ns). During the insulin clamp, glucose disposal rate was nearly identical in patients and controls (25.9±1.8 and 27.2±1.8 μmol kg^-1 min^-1, respectively, P=0.88). Non-oxidative glucose disposal accounted for similar proportions of total glucose uptake (59 versus 53%, patients versus controls, ns). Resting energy expenditure (13.7±0.6 versus 13.8±0.8 cal kg^-1 min^-1, ns) and insulin-induced thermogenesis were similar in the two groups. Fasting plasma NEFA concentrations (0.64±0.09 and 0.64±0.06 mmol l^-1, patients and controls, ns) fell in a similar time-course and to virtually identical nadirs (0.13±0.02 and 0.14±0.02 mmol l^-1) after insulin infusion. Fasting plasma potassium was similar in patients and controls (3.99±0.10 and 4.16±0.04 mmol l^-1, ns), and insulin induced equivalent hypokalaemia (-14 versus -19%). Conclusions. None of the in vivo actions of insulin were impaired in patients with when compared to matched controls. Therefore, we conclude that cardiological syndrome X is not an insulin resistant state per se, and that any decrease in insulin sensitivity found in this condition is likely to be secondary.     

Metabolic Abnormalities in Offspring of NIDDM Patients with a Family History of Diabetes Mellitus

NIDDM appears to be an inherited condition. Our aim was to identify early metabolic abnormalities in non-diabetic offspring with one NIDDM parent and with a strongly positive (n = 58, age 27.8 ± 7.0 years) or a negative family history (n = 38, age 27.4 ± 6.7 years) of diabetes. These were compared with 31 offspring of non-diabetic parents (age 26.9 ± 5.5 years). After an overnight fast, blood was taken for glucose, insulin, C-peptide, insulin receptors, and lipids. All the subjects underwent a 75 g oral glucose tolerance test. The positive family history group had significantly higher fasting levels of triglycerides (1.09 ± 0.24 vs control subjects: CS: 0.93 ± 0.16 mmol l⁻¹, p < 0.001), insulin (102.8 ± 46.4 vs CS: 77.5 ± 32.4 pmol l⁻¹, p < 0.01) and C-peptide (0.69 ± 0.22 vs CS: 0.61 ± 0.19 nmol l⁻¹, p < 0.05) and lower numbers of insulin receptors per red cell (9.1 × 10³ (4.5–18.1, 95 % confidence intervals) vs CS: (11.2 × 10³ (6.3–19.9)), p < 0.01, despite similar blood glucose levels. After a glucose challenge (120 min), the increases in both insulin and C-peptide concentrations were significantly greater in the positive family history group (289.2 ± 214.1 pmol l⁻¹, 2.23 ± 1.48 nmol l⁻¹), respectively, than in CS (192.4 ± 170.3 pmol l⁻¹, p < 0.05) (1.54 ± 0.99 nmol l⁻¹ p < 0.01), respectively. No significant differences were found in fasting and post-challenge glucose levels. The negative family history group had significantly lower numbers of insulin receptors 9.4 × 10³ (4.1–15.2) compared with CS (p < 0.05). Insulin sensitivity was significantly reduced in the positive family history group (41.6 %) compared with control subjects (51.9 %), p < 0.01. The results strongly support the familial basis of the disease.