Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians

Impaired glucose tolerance often presages the development of non-insulin-dependent diabetes mellitus. We have studied insulin action and secretion in 24 Pima Indians before and after the development of impaired glucose tolerance and in 254 other subjects representing the whole spectrum of glucose tolerance, including subjects with overt non-insulin-dependent diabetes. The transition from normal to impaired glucose tolerance was associated with a decrease in glucose uptake during hyperinsulinemia, from 0.018 to 0.016 mmol per minute (from 3.3 to 2.8 mg per kilogram of fat-free body mass per minute) (P less than 0.0003). Mean plasma insulin concentrations increased during an oral glucose-tolerance test, from 1200 to 1770 pmol per liter (from 167 to 247 microU per milliliter). In 151 subjects with normal glucose tolerance, the insulin concentration measured during an oral glucose-tolerance test correlated with the plasma glucose concentration (r = 0.48, P less than or equal to 0.0001). This relation was used to predict an insulin concentration of 1550 pmol per liter (216 microU per milliliter) in subjects with impaired glucose tolerance (actual value, 1590 pmol per liter [222 microU per milliliter]; P not significant), suggesting that these subjects had normal secretion of insulin. In contrast, plasma insulin concentrations in the diabetics decreased as glucose concentrations increased (r = -0.75, P less than or equal to 0.0001), suggesting deficient secretion of insulin. This relative insulin deficiency first appears at the lower end of the second (diabetic) mode seen in population frequency distributions of plasma glucose concentrations. Our data show that impaired glucose tolerance in our study population is primarily due to impaired insulin action. In patients with non-insulin-dependent diabetes mellitus, by contrast, impaired insulin action and insulin secretory failure are both present.     

Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy

To examine the extent to which the defect in insulin action in subjects with non-insulin-dependent diabetes mellitus (NIDDM) can be accounted for by impairment of muscle glycogen synthesis, we performed combined hyperglycemic-hyperinsulinemic clamp studies with [13C]glucose in five subjects with NIDDM and in six age- and weight-matched healthy subjects. The rate of incorporation of intravenously infused [1-13C]glucose into muscle glycogen was measured directly in the gastrocnemius muscle by means of a nuclear magnetic resonance (NMR) spectrometer with a 15.5-minute time resolution and a 13C surface coil. The steady-state plasma concentrations of insulin (approximately 400 pmol per liter) and glucose (approximately 10 mmol per liter) were similar in both study groups. The mean (+/- SE) rate of glycogen synthesis, as determined by 13C NMR, was 78 +/- 28 and 183 +/- 39 mumol-glucosyl units per kilogram of muscle tissue (wet weight) per minute in the diabetic and normal subjects, respectively (P less than 0.05). The mean glucose uptake was markedly reduced in the diabetic (30 +/- 4 mumol per kilogram per minute) as compared with the normal subjects (51 +/- 3 mumol per kilogram per minute; P less than 0.005). The mean rate of nonoxidative glucose metabolism was 22 +/- 4 mumol per kilogram per minute in the diabetic subjects and 42 +/- 4 mumol per kilogram per minute in the normal subjects (P less than 0.005). When these rates are extrapolated to apply to the whole body, the synthesis of muscle glycogen would account for most of the total-body glucose uptake and all of the nonoxidative glucose metabolism in both normal and diabetic subjects. We conclude that muscle glycogen synthesis is the principal pathway of glucose disposal in both normal and diabetic subjects and that defects in muscle glycogen synthesis have a dominant role in the insulin resistance that occurs in persons with NIDDM.     

Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance.

BACKGROUND: Insulin resistance and impaired insulin secretion both occur in non-insulin-dependent diabetes (NIDDM), but their relative importance is unclear. Hyperglycemia itself has adverse effects on tissue insulin sensitivity and insulin secretion that make it difficult to distinguish between primary and secondary abnormalities. To avoid this problem we studied subjects with postprandial glucose intolerance but not sustained hyperglycemia. METHODS: We compared the rate of systemic appearance and disappearance of glucose, the output of endogenous hepatic glucose, splanchnic and muscle uptake of glucose, and plasma insulin and glucagon responses after the ingestion of 1 g of glucose per kilogram of body weight in 15 subjects with impaired glucose tolerance (8 of them nonobese and 7 obese) and in 16 normal subjects (9 nonobese and 7 obese) who were matched for age and weight. RESULTS: After glucose ingestion the mean (+/- SE) rate of total systemic appearance of glucose was significantly higher in both the nonobese subjects (455 +/- 12 mmol per five hours) and the obese subjects (486 +/- 17 mmol per five hours) with impaired glucose tolerance than in the respective normal subjects (411 +/- 11 and 436 +/- 7 mmol per five hours). This difference was fully accounted for by the reduced suppression of endogenous hepatic glucose in the subjects with impaired glucose tolerance (a reduction of about 28 percent, vs. 48 percent in the normal subjects; P less than 0.01). Despite late hyperinsulinemia, at 30 minutes the subjects with impaired glucose tolerance had smaller increases in plasma insulin and smaller reductions in plasma glucagon (both P less than 0.01). Molar ratios of plasma insulin to plasma glucagon levels correlated inversely (r = -0.62, P less than 0.001) with the rates of systemic glucose appearance; the latter correlated positively (r = 0.72, P less than 0.0001) with peak plasma glucose concentrations. CONCLUSIONS: Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function. The late hyperinsulinemia may be the consequence of an inadequate early beta-cell response rather than of insulin resistance.     

Insulin resistance in essential hypertension

High blood pressure is prevalent in obesity and in diabetes, both conditions with insulin resistance. To test whether hypertension is associated with insulin resistance independently of obesity and glucose intolerance, we measured insulin sensitivity (using the euglycemic insulin-clamp technique), glucose turnover (using [3H]glucose isotope dilution), and whole-body glucose oxidation (using indirect calorimetry) in 13 young subjects (38 +/- 2 years [+/- SEM]) with untreated essential hypertension (165 +/- 6/112 +/- 3 mm Hg), normal body weight, and normal glucose tolerance. In the postabsorptive state, all measures of glucose metabolism were normal. During steady-state euglycemic hyperinsulinemia (about 60 microU per milliliter), hepatic glucose production and lipolysis were effectively suppressed, and glucose oxidation and potassium disposal were normally stimulated. However, total insulin-induced glucose uptake was markedly impaired (3.80 +/- 0.32 vs. 6.31 +/- 0.42 mg per minute per kilogram of body weight in 11 age- and weight-matched controls, P less than 0.001). Thus, reduced nonoxidative glucose disposal (glycogen synthesis and glycolysis) accounted for virtually all the defect in overall glucose uptake (1.19 +/- 0.24 vs. 3.34 +/- 0.44 mg per minute per kilogram, P less than 0.001). Total glucose uptake was inversely related to systolic or mean blood pressure (r = 0.76 for both, P less than 0.001). These results provide preliminary evidence that essential hypertension is an insulin-resistant state. We conclude that this insulin resistance involves glucose but not lipid or potassium metabolism, is located in peripheral tissues but not the liver, is limited to nonoxidative pathways of intracellular glucose disposal, and is directly correlated with the severity of hypertension.     

Insulin resistance and hyperinsulinemia in patients with thalassemia major treated by hypertransfusion

Diabetes mellitus in patients receiving hypertransfusion for thalassemia major is usually attributed to damage to beta cells. To determine whether iron overload leads to insulin resistance before the development of insulin deficiency, insulin was infused (by euglycemic insulin-clamp technique) into 12 children with thalassemia (4 of whom were prepubertal, and 8 pubertal) who had normal or only moderately impaired glucose tolerance and who were receiving chelation therapy. Although insulin-stimulated glucose metabolism in the prepubertal children with thalassemia was similar to that in controls (normal prepubertal children) (319 +/- 23 vs. 314 +/- 41 mg per square meter of body-surface area per minute, P not significant), the response to insulin was markedly impaired in the pubertal children with thalassemia (155 +/- 18 vs. 224 +/- 15 mg per square meter per minute in normal pubertal controls, P less than 0.01). Plasma insulin levels rose excessively after oral glucose administration in the pubertal subjects with thalassemia, but not in the prepubertal patients (P less than 0.001). Furthermore, in response to a standard hyperglycemic stimulus, insulin levels in the pubertal patients rose to two to three times greater than normal and C-peptide levels became significantly elevated. Our data suggest that insulin resistance and increased insulin secretion develop in older children with thalassemia treated with long-term hypertransfusion therapy before the development of diabetes.     

Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans

Pancreatic tissue obtained by hemipancreatectomy from healthy living related donors has been transplanted into recipients with Type I diabetes mellitus. To determine the metabolic consequences of this procedure for the donors, we carried out oral glucose-tolerance testing and 24-hour monitoring of serum glucose levels and urinary C-peptide excretion as a measure of insulin secretion in 28 donors, both before and one year after hemipancreatectomy. The mean fasting serum glucose level was significantly higher one year after the procedure (mean +/- SD, 5.4 +/- 0.9 vs. 4.9 +/- 0.5 mmol per liter; P less than 0.003), as was the serum glucose value two hours after the administration of glucose (8.7 +/- 2.9 vs. 6.5 +/- 1.0 mmol per liter; P less than 0.001). The fasting serum insulin level was significantly lower one year after hemipancreatectomy (33.0 +/- 21.6 vs. 38.4 +/- 21.6 pmol per liter; P less than 0.05), as was the area under the insulin curves during the oral glucose-tolerance test (52,554 +/- 22,320 vs. 76,230 +/- 33,354 pmol per liter per minute; P less than 0.04). The mean 24-hour serum glucose-profile value was higher at one year, and the 24-hour urinary C-peptide excretion was lower in the 17 donors who underwent these studies. Seven of the 28 donors had abnormal glucose tolerance one year after hemipancreatectomy; however, insulin secretion in these 7 donors was indistinguishable from that in the 21 donors who had normal glucose tolerance. All 28 donors had fasting serum glucose concentrations lower than 7.8 mmol per liter, and their mean 24-hour plasma glucose levels remained within the normal range. We conclude that in healthy donors hemipancreatectomy results in a deterioration of insulin secretion and glucose tolerance, as measured one year later. Further study is required to ascertain whether the development of clinical diabetes mellitus is a risk inherent in hemipancreatectomy.     

肥胖对不同糖耐量者第一时相胰岛素分泌功能的影响

 目的： 探讨肥胖对不同糖耐量人群第一时相胰岛素分泌功能的影响。方法： 无糖尿病家族史的正常糖耐量者(正常对照,NC)38例、2型糖尿病一级亲属正常糖耐量(NGT)者32例、糖调节受损(IGR)者67例及新诊断的2型糖尿病(T2DM)患者35例参与本试验。这4个组再分为超重/肥胖及正常体重2个亚组。各组均行静脉葡萄糖耐量试验（IVGTT）和口服葡萄糖-胰岛素释放试验（OG-IRT）,计算第一时相胰岛素分泌功能指数(AlR3-5)及胰岛素敏感性指数（ISI）,分析肥胖对不同糖耐量人群胰岛β细胞功能及胰岛素抵抗的影响。结果： NC超重/肥胖亚组较正常体重亚组AIR3-5显著升高（P<0.05）,其余3对亚组间比较差异均无统计学意义（均P>0.05）。超重/肥胖亚组ISI较正常体重亚组有降低趋势,其中IGR两亚组间比较差异无统计学意义（P>0.05）,其余3对亚组间比较差异均有统计学意义（均P<0.05）。ISI与体重指数和腰围在各组均呈负相关（P<0.05）,与AIR3-5在NC组呈负相关（P<0.05）,而在其余各组均呈正相关（均P<0.05）。结论： 肥胖对不同糖耐量人群胰岛β细胞分泌功能影响各不相同。无糖尿病家族史的正常糖耐量者随着胰岛素抵抗的加重,第一时相胰岛素分泌功能代偿性增加,而2型糖尿病一级亲属正常糖耐量者、糖调节受损者和2型糖尿病患者则不能代偿性增加。     

Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulin-dependent diabetes mellitus

To determine whether sulfonylureas and exogenous insulin have different effects on insulin action, we studied eight patients with non-insulin-dependent diabetes mellitus before and after three months of treatment with tolazamide and exogenous semisynthetic human insulin, using a randomized crossover design. Therapy with tolazamide and therapy with insulin resulted in similar improvement of glycemic control, as measured by a decrease in mean glycosylated hemoglobin (+/- SEM) from 9.4 +/- 0.7 percent to 7.7 +/- 0.5 percent with tolazamide and to 7.1 +/- 0.2 percent with exogenous insulin (P less than 0.01 for both comparisons). Therapy with either tolazamide or exogenous insulin resulted in a similar lowering (P less than 0.05) of postabsorptive glucose-production rates (from 2.3 +/- 0.1 to 2.0 +/- 0.2 and 1.8 +/- 0.1 mg per kilogram of body weight per minute, respectively) but not to normal (1.5 +/- 0.1 mg per kilogram per minute). Both tolazamide and exogenous insulin increased (P less than 0.05) glucose utilization at supraphysiologic insulin concentrations (from 6.2 +/- 0.7 to 7.7 +/- 0.6 mg per kilogram per minute with tolazamide and to 7.8 +/- 0.6 mg per kilogram per minute with exogenous insulin) to nondiabetic rates (7.9 +/- 0.5 mg per kilogram per minute). Neither agent altered erythrocyte insulin binding at physiologic insulin concentrations. We conclude that treatment with sulfonylureas or exogenous insulin results in equivalent improvement in insulin action in patients with non-insulin-dependent diabetes mellitus. Therefore, the choice between these agents should be based on considerations other than their ability to ameliorate insulin resistance.     

Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus.

BACKGROUND. Glucagon-like peptide-1 (7-36) amide (glucagon-like insulinotropic peptide, or GLIP) is a gastrointestinal peptide that potentiates the release of insulin in physiologic concentrations. Its effects in patients with diabetes mellitus are not known. METHODS. We compared the effect of an infusion of GLIP that raised plasma concentrations of GLIP twofold with the effect of an infusion of saline, on the meal-related release of insulin, glucagon, and somatostatin in eight normal subjects, nine obese patients with non-insulin-dependent diabetes mellitus (NIDDM), and eight patients with insulin-dependent diabetes mellitus (IDDM). The blood glucose concentrations in the patients with diabetes were controlled by a closed-loop insulin-infusion system (artificial pancreas) during the infusion of each agent, allowing measurement of the meal-related requirement for exogenous insulin. In the patients with IDDM, normoglycemic-clamp studies were performed during the infusions of GLIP and saline to determine the effect of GLIP on insulin sensitivity. RESULTS. In the normal subjects, the infusion of GLIP significantly lowered the meal-related increases in the blood glucose concentration (P less than 0.01) and the plasma concentrations of insulin and glucagon (P less than 0.05 for both comparisons). The insulinogenic index (the ratio of insulin to glucose) increased almost 10-fold, indicating that GLIP had an insulinotropic effect. In the patients with NIDDM, the infusion of GLIP reduced the mean (+/- SE) calculated isoglycemic meal-related requirement for insulin from 17.4 +/- 2.8 to 2.0 +/- 0.5 U (P less than 0.001), so that the integrated area under the curve for plasma free insulin was decreased (P less than 0.05) in spite of the stimulation of insulin release. In the patients with IDDM, the GLIP infusion decreased the calculated isoglycemic meal-related insulin requirement from 9.4 +/- 1.5 to 4.7 +/- 1.4 U. The peptide decreased glucagon and somatostatin release in both groups of patients. In the normoglycemic-clamp studies in the patients with IDDM, the GLIP infusion significantly increased glucose utilization (saline vs. GLIP, 7.2 +/- 0.5 vs. 8.6 +/- 0.4 mg per kilogram of body weight per minute; P less than 0.01). CONCLUSIONS. GLIP has an antidiabetogenic effect, and it may therefore be useful in the treatment of patients with NIDDM.     

2型糖尿病一级亲属不同糖耐量者第一时相胰岛素分泌功能的变化

目的：探讨胰岛素分泌功能和胰岛素抵抗（IR）在2型糖尿病（T2DM）发生、发展中的作用。 方法： T2DM一级亲属正常糖耐量（NGT+）组32例，T2DM一级亲属糖耐量异常（IGT+）组36例，新诊断的T2DM组35例，计算各组的第一时相胰岛素分泌功能指数（AIR3-5）及胰岛素敏感性指数（SIM），与无糖尿病家族史的正常糖耐量（NGT-）组（38例）比较。 结果： T2DM一级亲属T2DM组、IGT+和NGT+组AIR3-5均低于NGT-组（P值分别为<0.01、<0.01、＜0.05）；T2DM组和IGT+组SIM均低于NGT-组（均P<0.01），而NGT+组SIM值与NGT-组比较无统计学差异（P>0.05）。结论： 胰岛素分泌功能缺陷可能是T2DM发病的始动因素。当发展为IGT及T2DM时，胰岛素分泌功能进一步降低，并伴有胰岛素敏感性的降低。     

Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes

In fasting nondiabetic subjects, insulin is secreted in regular pulses every 12 to 15 minutes, but patients with non-insulin-dependent diabetes lack regular oscillatory insulin secretion. To investigate whether abnormal insulin oscillations are an early feature of diabetes, we studied 10 minimally glucose-intolerant first-degree relatives of patients with non-insulin-dependent diabetes and 10 controls matched for age and obesity. We performed a time-series analysis of fasting plasma insulin levels in blood samples obtained at 1-minute intervals for 150 minutes. Fasting plasma glucose levels were higher in the relatives than in the controls (mean +/- SD, 5.4 +/- 0.7 vs. 4.4 +/- 0.3 mmol per liter). Autocorrelation of pooled data showed no regular oscillatory activity in the relatives but a 13-minute cycle in the controls (r = 0.23, P less than 0.001). Similarly, Fourier transform analysis showed no significant peak in the relatives but the expected significant peak at 13 to 14 minutes in the controls (P less than 0.05). First-phase (0 to 10 minutes) insulin secretory responses to glucose administered intravenously were not significantly impaired in the relatives (geometric mean, 188 pmol per liter [26.2 mU per liter]; range of SD, +103 to -67 pmol per liter [+14.4 to -9.3 mU per liter]), as compared with the controls (geometric mean, 231 pmol per liter [32.2 mU per liter]; range of SD, +131 to -83 pmol per liter [+18.2 to -11.6 mU per liter]). We conclude that abnormal oscillatory insulin secretion may be an early phenomenon in the development of non-insulin-dependent diabetes.     

Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus

We infused small doses of insulin (0.3 mU per kilogram of body weight per minute; range, 0.9 to 1.7 U per hour) for three hours into 8 subjects who did not have diabetes, 11 patients with well-controlled diabetes (hemoglobin A1, 7.6 +/- 0.7 percent), and 10 patients with poorly controlled diabetes (hemoglobin A1, 11.5 +/- 1.7 percent) to simulate the mild peripheral hyperinsulinemia observed during insulin treatment. Normoglycemia was established in the patients during the night before study. During the insulin infusion, the plasma glucose level stabilized at 60 to 70 mg per deciliter (3.3 to 3.9 mmol per liter) in the subjects without diabetes and the patients with poorly controlled diabetes, because of a rebound increase in hepatic glucose production. In contrast, hypoglycemia developed in the patients with well-controlled diabetes (42 +/- 2 mg of glucose per deciliter, or 2.3 +/- 0.1 mmol per liter, P less than 0.01) as glucose production remained suppressed. The hypoglycemia in the patients with well-controlled diabetes was associated with a lowering of the plasma threshold of glucose that triggered a release of epinephrine (less than 45 mg of glucose per deciliter, or 2.5 mmol per liter, vs. greater than 55 mg per deciliter, or 3.1 mmol per liter, in the other groups, P less than 0.01) as well as an enhanced sensitivity to the suppressive effects of insulin on hepatic glucose production. Nearly identical disturbances in glucose counterregulation and decreased perception of hypoglycemia developed when four of the subjects with poorly controlled diabetes were restudied after intensive treatment. We conclude that strict control of diabetes induces physiologic alterations (delayed release of epinephrine and persistent suppression of glucose production) that impair glucose counterregulation to doses of insulin in the therapeutic range. These defects may contribute to the increased incidence of severe hypoglycemia reported during intensive insulin therapy.     

Nibbling versus gorging: metabolic advantages of increased meal frequency

We studied the effect of increasing the frequency of meals on serum lipid concentrations and carbohydrate tolerance in normal subjects. Seven men were assigned in random order to two metabolically identical diets. One diet consisted of 17 snacks per day (the nibbling diet), and the other of three meals per day (the three-meal diet); each diet was followed for two weeks. As compared with the three-meal diet, the nibbling diet reduced fasting serum concentrations of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B by a mean (+/- SE) of 8.5 +/- 2.5 percent (P less than 0.02), 13.5 +/- 3.4 percent (P less than 0.01), and 15.1 +/- 5.7 percent (P less than 0.05), respectively. Although the mean blood glucose level and serum concentrations of free fatty acids, 3-hydroxybutyrate, and triglyceride were similar during both diets, during the nibbling diet the mean serum insulin level decreased by 27.9 +/- 6.3 percent (P less than 0.01) and the mean 24-hour urinary C-peptide output decreased by 20.2 +/- 5.6 percent (P less than 0.02). In addition, the mean 24-hour urinary cortisol excretion was lower by 17.3 +/- 5.9 percent (P less than 0.05) at the end of the nibbling diet than at the end of the three-meal diet. The blood glucose, serum insulin, and C-peptide responses to a standardized breakfast and the results of an intravenous glucose-tolerance test conducted at the end of each diet were similar. We conclude that in addition to the amount and type of food eaten, the frequency of meals may be an important determinant of fasting serum lipid levels, possibly in relation to changes in insulin secretion.     

Accentuated vascular and endocrine response to SQ 20881 in hypertension.

We assessed vascular and hormonal responses to inhibition of peptidyldipeptide hydrolase, which converts angiotensin I to angiotensin II (converting enzyme) and degrades bradykinin (kininase II), in subjects given 10 meq of sodium to activate both systems. In nine normal subjects a threshold dose of 30 MICROgram per kilogram of the inhibitor, SQ 20881, modestly influenced mean blood pressure (-5 +/- 1 mm Hg, P less than 0.05), and renal blood flow (+50+/-8 ml per 100 g per minute), plasma renin activity (+ 2.3 +/- 0.6 ng per milliliter per hour), and angiotensin II (-11 +/- 3 pg per milliliter) more strikingly (P less than 0.01). In six patients with essential hypertension the threshold inhibitor dose was reduced to 10 microgram per kilogram; 30 kilogram per kilogram had an enhanced (P less than 0.01) effect on mean blood pressure (-11 +/- 2 mm Hg), renal blood flow (137 +/- 20 ml per 100 g per minute), and angiotensin II concentration (-29 +/- 12 pg per milliliter). SQ 20881 elevated plasma bradykinin concentration (7.4 +/- 2.6 ng per milliliter, P less than 0.02) only in the hypertensive patients. Because both renin-angiotensin and kallikrein-bradykinin systems are influenced, vascular responses to SQ 20881 must be interpreted cautiously, but this agent has excellent antihypertensive characteristics.     

A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension

It has been suggested that the metabolic side effects of antihypertensive drugs are responsible for their failure to reduce cardiovascular morbidity in patients with hypertension. Therefore, in 50 patients with essential hypertension, we performed a randomized, double-blind, crossover study comparing the effects of carbohydrate and lipid metabolism of captopril (mean [+/- SD] dose, 81 +/- 24 mg per day) and hydrochlorothiazide (40 +/- 12 mg per day) over two four-month treatment periods. Captopril increased the insulin-mediated disposal of glucose, as compared with placebo, from 5.7 +/- 2.4 to 6.3 +/- 2.5 mg per kilogram of body weight per minute (P less than 0.05), whereas hydrochlorothiazide caused a decrease from 6.4 +/- 2.0 to 5.7 +/- 1.9 (P less than 0.01). Captopril had no effect on the basal insulin concentration, but it decreased the late (30- to 90-minute) insulin response to glucose and increased the early (2- to 6-minute) insulin peak. Hydrochlorothiazide increased the basal insulin concentration and the late insulin response to glucose. These findings may be explained by an increase in insulin sensitivity with captopril and a decrease with hydrochlorothiazide. Little or no change was seen in serum lipid or lipoprotein levels during treatment with captopril, whereas hydrochlorothiazide caused significant increases in serum total (5 percent) and low-density lipoprotein (6 percent) cholesterol levels and total (15 percent) and very-low-density lipoprotein (25 percent) triglyceride levels, as compared with placebo (P less than 0.01 for all comparisons). We conclude that hydrochlorothiazide for the treatment of essential hypertension has adverse effects on glucose and lipid metabolism. It is possible, but not proved in this study, that these changes may contribute to the risk for diabetes mellitus and coronary heart disease. In contrast, captopril appears to have beneficial or no effects on glucose and lipid metabolism.     

The effects of biosynthetic human proinsulin on carbohydrate metabolism in non-insulin-dependent diabetes mellitus

We compared the glucose-lowering effect of proinsulin, the precursor molecule of insulin, with that of insulin itself. In patients with non-insulin-dependent diabetes mellitus (NIDDM) in whom proinsulin (0.2 U per kilogram of body weight) was subcutaneously injected at 9 a.m., fasting glucose levels (247 +/- 22 mg per deciliter [+/- SEM]) became normal within six hours and elevated rates of hepatic glucose output were lowered. The response to regular insulin (0.2 U per kilogram) was of similar magnitude but faster. Glucose clearance was stimulated less by proinsulin, reflecting its preferential action in suppressing glucose output. Hypoglycemia occurred in five of nine insulin-treated patients, but in only one of nine proinsulin-treated patients. After proinsulin injection at bedtime (30.5 +/- 4 U), serum proinsulin concentrations reached a peak by five hours and declined gradually thereafter. Fasting hepatic glucose output became normal, and euglycemia was sustained without overnight hypoglycemia. Proinsulin reduced plasma glucose more effectively than an equal unit dosage of NPH insulin, but since higher doses of NPH insulin were not used, no conclusions could be drawn about the relative desirability of these preparations for clinical use. We conclude that subcutaneously injected proinsulin has prolonged pharmacokinetics in plasma and can normalize plasma glucose in NIDDM characterized by severe hyperglycemia; as compared with the hypoglycemic effects of regular insulin, those of proinsulin are mostly due to suppression of hepatic glucose output, with little stimulation of glucose disposal and less hypoglycemia; and proinsulin may have a role in the treatment of NIDDM.     

Low urinary chiro-inositol excretion in non-insulin-dependent diabetes mellitus

BACKGROUND and METHODS. Inositol is a major component of the intracellular mediators of insulin action. To investigate the possible role of altered inositol metabolism in non-insulin-dependent diabetes mellitus (NIDDM), we used gas chromatography and mass spectrometry to measure the myo-inositol and chiro-inositol content of urine specimens from normal subjects and patients with NIDDM. The study subjects were whites, blacks, and Pima Indians. The type of inositol and its concentration in insulin-mediator preparations from muscle-biopsy specimens from normal subjects and diabetic patients were also determined. RESULTS. The urinary excretion of chiro-inositol was much lower in the patients with NIDDM (mean [+/- SE], 1.8 +/- 0.8 mumol per day) than in the normal subjects (mean, 84.9 +/- 26.9 mumol per day; P less than 0.01). In contrast, the mean urinary myo-inositol excretion was higher in the diabetic patients than in the normal subjects (444 +/- 135 vs. 176 +/- 46 mumol per day; P less than 0.05). There was no correlation between chiro-inositol excretion and the age, sex, or weight of the diabetic patients, nor was there any correlation between urinary chiro-inositol and myo-inositol excretion in either group. The results were similar in a primate model of NIDDM, and chiro-inositol excretion was decreased to a lesser extent in animals with prediabetic insulin resistance. chiro-Inositol was undetectable in insulin-mediator preparations from muscle-biopsy samples obtained from patients with NIDDM. Similar preparations from normal subjects contained substantial amounts of chiro-inositol. Furthermore, the chiro-inositol content of such preparations increased after the administration of insulin during euglycemic-hyperinsulinemic-clamp studies in normal subjects but not in patients with NIDDM. CONCLUSIONS. NIDDM is associated with decreased chiro-inositol excretion and decreased chiro-inositol content in muscle. These abnormalities seem to reflect the presence of insulin resistance in NIDDM.     

Optimal rate of enteral glucose administration in children with glycogen storage disease type I

Rates of administration of enteral carbohydrate to maintain the plasma glucose concentration and suppress organic acidemia in young children with glycogen storage disease Type I have not been clearly established. Therefore, we studied six children with the disease during sequential nasogastric infusions of carbohydrate at four different rates (10.5, 8.6, 5.8, and 3 mg of carbohydrate per kilogram of body weight per minute). The rates at which total and endogenous glucose appeared in the plasma were measured with [2H2] glucose. The infusion rates of carbohydrate were linearly correlated (r = 0.88, P less than 0.001) with the plasma glucose concentration, which was about 90 mg per deciliter at a rate of 8.6 mg per kilogram per minute. The mean (+/- SE) rate of appearance of endogenous glucose was 1.4 +/- 0.1 mg per kilogram per minute at a nasogastric infusion rate of 5.8 mg of carbohydrate per kilogram per minute (a rate similar to that of hepatic glucose production in normal children who have fasted overnight), and was completely suppressed at 10.5 mg of carbohydrate per kilogram per minute. Concentrations of plasma lactate, pyruvate, free fatty acids, and ketone bodies were inversely related to the rate of carbohydrate administration below 8.6 mg per kilogram per minute. We conclude that the minimal nocturnal nasogastric infusion rate of carbohydrate needed to maintain plasma glucose concentrations and minimize organic acidemia in young children with glycogen storage disease Type I is approximately 8 to 9 mg per kilogram per minute.     

Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes

Patients with insulin-dependent diabetes mellitus often have poor metabolic control during puberty. To determine whether puberty is associated with decreased insulin-stimulated glucose metabolism, we compared the results of euglycemic insulin-clamp studies in adults and prepubertal and pubertal children with and without insulin-dependent diabetes. In nondiabetic pubertal children, insulin-stimulated glucose metabolism (201 +/- 12 mg per square meter of body surface area per minute) was sharply reduced, as compared with that of prepubertal children and adults (316 +/- 34 and 290 +/- 21 mg per square meter, respectively; P less than 0.01), despite comparable hyperinsulinemia (insulin levels of 80 to 90 microU per milliliter). Similarly, the response to insulin was 25 to 30 percent lower in the diabetic pubertal children than in the diabetic prepubertal children (P less than 0.05) and adults (P = 0.07). At each stage of development, the stimulating effect of insulin on glucose metabolism was decreased by 33 to 42 percent in the children with diabetes (P less than 0.01). In all the groups of children studied, the response to insulin was inversely correlated with mean 24-hour levels of growth hormone (r = -0.52, P = 0.01). Among the diabetic children, the glycosylated hemoglobin levels were substantially higher in the pubertal children than in the prepubertal children (P less than 0.02), although the daily insulin doses tended to be higher. These data suggest that insulin resistance occurs during puberty in both normal children and children with diabetes. The combined adverse effects of puberty and diabetes on insulin action may help explain why control of glycemia is so difficult to achieve in adolescent patients.     

Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance

We studied the relation of serum insulin levels to plasma lipid levels and blood pressure in two groups drawn from among 247 healthy, normotensive nonobese subjects with normal glucose tolerance. One group of 32 subjects was defined as having hyperinsulinemia (serum insulin, greater than 2 SD above the mean) and then compared with 32 normoinsulinemic subjects (serum insulin within 1 SD of the mean) matched for age (mean, 39 years), sex (22 men and 10 women), and body-mass index (24.7). The two groups had similar patterns of smoking, drinking, and physical exercise. Plasma glucose levels after an oral glucose challenge were significantly higher (P less than 0.05) in the hyperinsulinemic group. In addition, the mean (+/- SEM) fasting plasma triglyceride levels in subjects with hyperinsulinemia were significantly higher (1.73 +/- 0.2 vs. 1.24 +/- 0.1 mmol per liter) and the plasma high-density lipoprotein cholesterol concentrations were lower (1.21 +/- 0.06 vs. 1.43 +/- 0.06 mmol per liter) than in subjects with normoinsulinemia. Both systolic (126 vs. 119 mm Hg; P less than 0.05) and diastolic (85 vs. 78 mm Hg; P less than 0.01) blood pressures were significantly elevated in the group with hyperinsulinemia. We conclude that healthy persons with hyperinsulinemia and normal glucose tolerance have an increase in risk factors for coronary artery disease, as compared with a well-matched group of healthy subjects with normal insulin levels.