Cardiovascular, metabolic and hormonal responses to the progressive exercise performed to exhaustion in patients with type 2 diabetes treated with metformin or glyburide.

OBJECTIVES: To evaluate the effects of Metformin and Glyburide on cardiovascular, metabolic and hormonal parameters during progressive exercise performed to exhaustion in the post-prandial state in women with type 2 diabetes (T2DM). DESIGN AND METHODS: Ten T2DM patients treated with Metformin (M group), 10 with Glyburide (G group) and 10 age-paired healthy subjects exercised on a bicycle ergometer up to exercise peak. Cardiovascular and blood metabolic and hormonal parameters were measured at times -60 min, 0 min, exercise end, and at 10 and 20 minutes of recovery phase. Thirty minutes before the exercise, a standard breakfast was provided to all participants. The diabetic patients took Metformin or Glyburide before or with meal. RESULTS: Peak oxygen uptake (VO(2)) was lower in patients with diabetes. Plasma glucose levels remained unchanged, but were higher in both diabetic groups. Patients with diabetes also presented lower insulin levels after meals and higher glucagon levels at exercise peak than C group. Serum cortisol levels were higher in G than M group at exercise end and recovery phase. Lactate levels were higher in M than G group at fasting and in C group at exercise peak. Nor epinephrine, GH and FFA responses were similar in all 3 groups. CONCLUSION: Progressive exercise performed to exhaustion, in the post-prandial state did not worsen glucose control during and after exercise. The administration of the usual dose of Glyburide or Metformin to T2DM patients did not influence the cardiovascular, metabolic and hormonal response to exercise.

The effects of metformin and glibenclamide on glucose metabolism, counter-regulatory hormones and cardiovascular responses in women with Type 2 diabetes during exercise of moderate intensity.

AIMS: To compare the effects of metformin and glibenclamide on cardiovascular, metabolic and hormonal parameters during exercise of moderate intensity performed in the postprandial state, in women with Type 2 diabetes. METHODS: Ten patients treated with metformin, 10 with glibenclamide and 10 control subjects (C) exercised on a bicycle ergometer at 50% of oxygen uptake (VO(2)) peak for 45 min. Cardiovascular, blood metabolic and hormonal parameters were determined at times -60 min (fasting), 0, +15, +30, +45 min (exercise) and at +60, +90 min (recovery). Thirty minutes prior to exercise, participants consumed a standard breakfast. Patients with diabetes took metformin or glibenclamide before the meal. RESULTS: Systolic and diastolic blood pressure and plasma glucose were higher in both diabetic groups, for the whole experiment. Blood glucose did not change during exercise in the three groups and increased at recovery only in the control group. Plasma glucagon concentrations at the end of exercise and recovery, and plasma lactate concentrations at recovery were higher in the metformin group. Insulin, noradrenaline, growth hormone, cortisol and free fatty acid responses were similar in all three groups. CONCLUSIONS: Our results suggest that the usual dose of glibenclamide and metformin can be taken safely before postprandial exercise of moderate intensity without affecting cardiovascular, metabolic and hormonal responses. However, after exercise, glibenclamide and metformin prevent the normal rise in blood glucose and metformin delays the fall in plasma lactate concentrations.

Association of acanthosis nigricans with race and metabolic disturbances in obese women

Acanthosis nigricans (AN) has been recognized as a marker of insulin resistance and diabetes mellitus. We have compared frequency of race and metabolic disturbances in obese women with several degrees of AN (AN group, N = 190) to a group without AN (non-AN group, N = 61) from a mixed racial population. The groups were similar regarding age and body mass index. All patients (except the diabetic patients) underwent an oral glucose tolerance test (75 g). The racial distribution of this population was 35.1 percent white, 37.8 percent mulatto and 27.1 percent black and the frequency of AN was 62.5, 82.1 and 83.8 percent, respectively, higher in black versus white (P = 0.003) and mulatto versus white (P = 0.002) women. The frequencies of diabetes mellitus and impaired glucose tolerance were 5.8 and 12.6 percent in the AN group and 1.6 and 8.2 percent in the non-AN group, respectively (P>0.05). Fasting glucose, ß cell function determined by the homeostasis model of assessment (HOMA), fasting insulin and insulin area under the curve were similar for the AN and non-AN groups. A higher HOMA insulin resistance was observed in the AN group compared to the non-AN group (P = 0.02) and in the subgroup of highest degree of AN compared to those with other degrees. The mean lipid levels and the frequency of dyslipidemia were similar for the two groups. AN was strongly associated with the black or mulatto rather than the white race, even after taking into account the effect of age, body mass index and HOMA insulin resistance

Association of acanthosis nigricans with race and metabolic disturbances in obese women.

Acanthosis nigricans (AN) has been recognized as a marker of insulin resistance and diabetes mellitus. We have compared frequency of race and metabolic disturbances in obese women with several degrees of AN (AN group, N = 190) to a group without AN (non-AN group, N = 61) from a mixed racial population. The groups were similar regarding age and body mass index. All patients (except the diabetic patients) underwent an oral glucose tolerance test (75 g). The racial distribution of this population was 35.1% white, 37.8% mulatto and 27.1% black and the frequency of AN was 62.5, 82.1 and 83.8%, respectively, higher in black versus white (P = 0.003) and mulatto versus white (P = 0.002) women. The frequencies of diabetes mellitus and impaired glucose tolerance were 5.8 and 12.6% in the AN group and 1.6 and 8.2% in the non-AN group, respectively (P>0.05). Fasting glucose, beta cell function determined by the homeostasis model of assessment (HOMA), fasting insulin and insulin area under the curve were similar for the AN and non-AN groups. A higher HOMA insulin resistance was observed in the AN group compared to the non-AN group (P = 0.02) and in the subgroup of highest degree of AN compared to those with other degrees. The mean lipid levels and the frequency of dyslipidemia were similar for the two groups. AN was strongly associated with the black or mulatto rather than the white race, even after taking into account the effect of age, body mass index and HOMA insulin resistance.

Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects.

Obesity is commonly associated with elevated plasma free fatty acid (FFA) levels, as well as with insulin resistance and hyperinsulinemia, two important cardiovascular risk factors. What causes insulin resistance and hyperinsulinemia in obesity remains uncertain. Here, we have tested the hypothesis that FFAs are the link between obesity and insulin resistance/hyperinsulinemia and that, therefore, lowering of chronically elevated plasma FFA levels would improve insulin resistance/hyperinsulinemia and glucose tolerance in obese nondiabetic and diabetic subjects. Acipimox (250 mg), a long-acting antilipolytic drug, or placebo was given overnight (at 7:00 P.M., 1:00 A.M., 7:00 A.M.) to 9 lean control subjects, 13 obese nondiabetic subjects, 10 obese subjects with impaired glucose tolerance, and 11 patients with type 2 diabetes. Euglycemic-hyperinsulinemic clamps and oral glucose tolerance tests (75 g) were performed on separate mornings after overnight Acipimox or placebo treatment. In the three obese study groups, Acipimox lowered fasting levels of plasma FFAs (by 60-70%) and plasma insulin (by approximately 50%). Insulin-stimulated glucose uptake during euglycemic-hyperinsulinemic clamping was more than twofold higher after Acipimox than after placebo. Areas under the glucose and insulin curves during oral glucose tolerance testing were both approximately 30% lower after Acipimox administration than after placebo. We conclude that lowering of elevated plasma FFA levels can reduce insulin resistance/hyperinsulinemia and improve oral glucose tolerance in lean and obese nondiabetic subjects and in obese patients with type 2 diabetes.

Mechanism of the diabetogenic action of cyclosporin A.

To investigate the mechanism of diabetogenic action of cyclosporin A (CsA), 7 male Wistar albino rats received 10 mg/kg/day of the drug for 4 weeks (CsA). The results were compared with controls (C); blood CsA levels measured weekly remained stable throughout the experiment (mean +/- SEM) (X = 2657.9+/-155.1 ng/ml). Intravenous glucose load (0.75 g/kg) performed after 2 weeks of CsA therapy showed glucose intolerance in treated animals as evaluated by the glucose area under the curve (CsA = 409.2+/-17.8 vs. C = 313.3+/-12.6 umol x ml(-1) x min(-1)) (p < 0.05) with insulin levels being similar in the two groups (CsA = 8603.9+/-1645.5 vs. C = 9571.9+/-828.5 pmol x ml(-1) x min(-1)). After 4 weeks of CsA administration, glucose intolerance was maintained (CsA = 398.6+/-35.6 vs. C = 301.7+/-23.0 umol x ml(-1) x min(-1)) (p < 0.05) associated with a significant decrease in insulin secretion (CsA = 4404.9+/-2392.0 vs. C = 10075.9+/-2861.0 pmol x ml(-1) x min(-1) (p < 0.05). These results suggest that CsA induced a state of insulin resistance preceding the failure of insulin secretion. After 4 weeks, the pancreatic insulin content was also decreased (CsA = 0.7+/-0.1 vs. C = 1.4+/-0.5 mU/mg) (p < 0.05). Maximal insulin binding to isolated adipocytes was not affected by CsA (CsA = 7.4+/-2.6 vs. C = 6.4+/-2.0%), although glucose transport and oxidation decreased after CsA treatment (p < 0.05). In conclusion, glucose intolerance induced by CsA in Wistar albino rats is due to decreased insulin production and impaired insulin action by a post-binding mechanism.

Human insulin allergy-immediate and late type III reactions in a long-standing IDDM patient.

UNLABELLED: Human insulin allergy-immediate or late type III reaction-is a rare event. We report the case of a 33-year-old female patient with insulin-dependent diabetes mellitus for 25 years who presented, in the last 8 years, mild but generalized urticaria partially controlled with oral antihistamines. There was no improvement after changing from mixed beef-pork to human insulin. In the last 3 years another allergic manifestation began: small, localized, subdermal and painful non-erythematous nodules with central hematomas at injection sites, occurring 6-8 h after the insulin injection and lasting for 48 h. The following maneuvers had no benefit: (1) Human insulin (NPH or Lente) administered with dexametasone or xylocain locally, (2) Short acting human insulin with or without previous boiling, (3) Anti-histamine cetirizine dihydrochloride-10 mg/day. The allergic symptoms disappeared only after treatment with short acting human insulin (up to 100 U/day) associated to prednisone-40 mg/day and cetirizine dihydrochloride for 4 months. However, after stopping prednisone the urticaria reappeared and it was relieved with insulin desensitization. The pain at the site of injections persisted. CONCLUSION: This long-standing IDDM patient presented two types of reactions to human insulin: the immediate type (systemic urticaria), treated with antihistamines and desensitization, and the Arthus' type III reaction (nodules and hematomas occurring 6-8 h after the insulin injection) that required glucocorticoid therapy for more than 4 months.

Insulin resistance in limb and trunk partial lipodystrophy (type 2 Köbberling-Dunnigan syndrome).

We studied insulin action in two patients with limb and trunk partial lipodystrophy with hirsutism and acanthosis nigricans. Glucose was normal in one of the patients and slightly above normal in the other during an oral glucose tolerance test (OGTT). An intravenous glucose tolerance test (IVGTT) was normal in both patients. Basal and glucose-stimulated insulin levels were elevated in both the OGTT and IVGTT in both patients. The response of plasma glucose to exogenously administered insulin was decreased. A euglycemic-hyperinsulinemic clamp performed in patient no. 2 indicated insulin resistance, which was not corrected by reducing the increased basal level of serum free fatty acids (FFAs). Binding of insulin to neck adipocytes was normal in both subjects, but glucose transport and oxidation in these cells was impaired. Insulin binding to abdominal adipocytes was increased in one patient whose adipocytes displayed higher glucose transport at low insulin concentrations. Glucose oxidation was decreased in abdominal adipocytes of both patients. We conclude that insulin resistance in Köbberling-Dunnigan type 2 partial lipodystrophy is not related to an alteration of the insulin molecule or to changes in insulin binding, but is more likely associated with a postreceptor defect, since glucose oxidation was impaired in adipocytes of the neck and abdomen.

Ultrasonographic abnormalities of the pancreas in IDDM and NIDDM patients.

OBJECTIVE: To evaluate the relationship between the type and duration of diabetes and pancreas size by ultrasonography. RESEARCH DESIGN AND METHODS: Pancreas images of 40 IDDM and 36 NIDDM patients with 0.3-34 yr of disease were compared with those of 60 normal healthy control subjects. RESULTS: The diameters +/- SD of the head, body, and tail of the pancreas in IDDM patients (1.9 +/- 0.3; 0.9 +/- 0.2; and 1.4 +/- 0.2 cm, respectively) were smaller than in NIDDM patients (2.7 +/- 0.4; 1.2 +/- 0.3; and 1.8 +/- 0.4 cm, respectively) and control group subjects (2.4 +/- 0.4; 1.1 +/- 0.3; and 1.8 +/- 0.4 cm, respectively). The pancreatic shrinkage in IDDM patients was clearly evident after 10 yr of the disease. NIDDM patients and control subjects had similar pancreatic dimensions, except for a greater body thickness in NIDDM patients with > 10 yr of disease (1.2 +/- 0.4 vs. 1.1 +/- 0.3 cm). These results were not related to differences in age, sex, and body size. Pancreas image was hypoechogenic in 72.5% of IDDM patients and hyperechogenic in 83.3% of NIDDM patients. CONCLUSIONS: Smaller pancreases in IDDM patients in comparison with NIDDM patients and control subjects were clearly demonstrated only after 10 yr of disease. Patients with NIDDM were not affected by pancreatic dimensions, except for a greater body thickness after 10 yr of disease. Pancreatic echogenicity increased with age.

Metabolic derangements in excessive insulin and sulfonylurea therapy.

Mild streptozotocin diabetic rats, characterized by normal or slightly elevated fasting blood glucose levels and glucose intolerance, treated with excessive doses of monocomponent pork insulin (0.5 U/day) (I) or glybenclamide (0.6 mg/day) (S) were compared to controls (C) and streptozotocin-diabetic rats without treatment (D). Intravenous glucose tolerance tests (0.75 g/kg) were performed in all animals and repeated after overtreatment. Insulin binding and insulin-induced D-(U-14C)-glucose transport and oxidation were also determined in isolated epididymal adipocytes. Diabetic rats showed a failure in the initial phase of insulin release and glucose intolerance as compared with (C). In overtreated rats glucose tolerance worsened (p < 0.05) after therapy. Maximal insulin binding by isolated adipocytes at tracer insulin concentration was unchanged after excessive insulin or sulfonylurea therapy. Besides, glucose transport and oxidation in the cells of overtreated rats were greater than in D and even greater than in C. These apparently divergent results, i.e. deterioration of glucose tolerance with increased insulin action in adipocytes suggest that overtreatment induces a state of resistance to hormone action in other target tissue(s) than the adipose one, possibly muscle.

The effects of glibenclamide treatment on insulin secretion and on insulin binding to erythrocytes in type II diabetes mellitus.

1. Eleven patients with type II diabetes mellitus were studied prior to, and after short- (10 days) and long-term (6 months) glibenclamide treatment. 2. A marked decrease in glucose level was observed after short- and long-term therapy using the oral glucose tolerance test (OGTT) and diet test (DT). 3. After short-term therapy, insulin level increased by 52.5% with the OGTT and by 37.6% with the DT; after long-term therapy, the increases were 78.6% and 69.5%, respectively. 4. Insulin binding to erythrocytes was unchanged by short- or long-term glibenclamide therapy. 5. These data suggest that the hypoglycemic effect of glibenclamide results from an increase in insulin secretion and that extrapancreatic actions at the receptor or post-receptor level are not necessarily involved.

Effects of a high-carbohydrate diet on blood glucose, insulin and triglyceride levels in normal and obese subjects and in obese subjects with impaired glucose tolerance.

1. The present study was performed in order to assess the influence of a high-carbohydrate diet on carbohydrate and lipid metabolism in humans. 2. Short-term (3 weeks) and long-term (6 weeks) effects of a high-carbohydrate diet (HCD, 85% carbohydrate) were compared with the effects of 2 weeks on a diet of normal carbohydrate content (ND, 45% carbohydrate). The study was conducted on 4 normal and 11 obese subjects (with normal or impaired glucose tolerance) on a metabolic ward. Fasting blood glucose, insulin and triglyceride levels were measured twice a week. Tolerance to carbohydrates was evaluated by measuring blood glucose and insulin levels after oral and intravenous glucose loads and liquid meals at intervals throughout the 8-week period. 3. Long-term HCD improved the tolerance to oral glucose, i.e., it decreased serum glucose and insulin responses to an oral glucose load. 4. HCD had no effects on fasting levels of glucose or insulin or on the tolerance to an intravenous glucose load. 5. A high-carbohydrate liquid meal induced greater post-prandial glucose and insulin levels than a normal liquid meal. 6. In a second group of 6 normal and 6 obese subjects, efficacy of the liquid meal tests was evaluated. A high-carbohydrate liquid meal induced greater glucose and insulin responses than a normal liquid meal during both dietary periods. 7. Fasting triglyceride levels increased and remained high throughout the HCD period.

Familial recurrence of geleophysic dysplasia.

We describe a girl with the manifestations of geleophysic dwarfism: small stature, a peculiar but pleasant and good-natured facial appearance, a dysostosis-multiplex-like bone dysplasia affecting predominantly hands and feet, hepatomegaly and stenosis, and insufficiency of the aortic valve. The proposita's sister died of heart failure at 3 years and was reported by the mother to have been a tiny child with small hands.

Department of Medicina, Faculdade de Medicina da Universidade de São Paulo, Brazil.

The acute and late phases of insulin secretion were studied in mongrel dogs before and after the induction of mild alloxan diabetes. Fasting glucose and insulin levels were unchanged from pretreatment values. The alloxan-diabetic dogs had significantly decreased early-phase insulin responses to glucose pulses (0.5 gm./kg.) and slower plasma glucose disappearance rates. In contrast, these mildly diabetic dogs achieved comparable insulin levels and higher glucose levels during a four-hour 40 mg./min. glucose infusion than pre-alloxan control values. Similar findings in human congenital mild diabetes have been interpreted as beta cell insensitivity or impedance to efficiency of plasma glucose uptake. The present observations in alloxan-induced mild diabetes in dogs suggest that reduced early-phase secretion and intact later phase of insulin secretion are not dependent on genetic determinants and may be induced in a model of acquired diabetes.