Relationships among natriuresis, atrial natriuretic peptide and insulin in insulin-dependent diabetes.

Insulin-dependent diabetic patients have a large exchangeable body sodium pool, secondary to sodium retention. The pathogenesis of impaired natriuresis in insulin dependent diabetes remains to be elucidated. The present study examines the role of hyperinsulinemia, impaired atrial natriuretic release, and resistance to atrial natriuretic peptide action in determining sodium retention in normotensive and hypertensive insulin-dependent diabetic patients. Eight insulin-dependent diabetic patients had significantly higher daily sodium excretion rate (147 +/- 16 mmol/day; mean +/- SE) during conventional insulin treatment (daily plasma glucose: 11.6 +/- 1.2 mmol/liter; daily plasma insulin: 27 +/- 3 microU/ml) than during intensified insulin treatment (daily sodium excretion rate: 91 +/- 12, P less than 0.01; daily plasma glucose: 6.8 +/- 0.7, P less than 0.01; daily plasma insulin: 44 +/- 4, P less than 0.01). Daily sodium excretion rate was also significantly lower (107 +/- 13, P less than 0.01) in the same diabetic patients during intensified insulin treatment along with hyperglycemic clamp (daily plasma glucose: 12.8 +/- 0.3, NS; plasma insulin 48 +/- 4, P less than 0.01). Seven control subjects had lower extracellular liquid volume than eight insulin-dependent diabetic patients (11.0 +/- 0.8 l/1.73 m2 vs. 14.8 +/- 0.9, P less than 0.05) and also had baseline plasma atrial natriuretic peptide concentrations (18 +/- 5 pg/ml vs. 37 +/- 4, P less than 0.05). Atrial natriuretic peptide response to saline challenge was blunted in insulin-dependent diabetic patients when saline was administered on the basis of body surface area (90 mmol/1.73 m2.90 min) but not when administered on the basis of extracellular liquid volume (ECV) (8.2 mmol/liter ECV.90 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type I diabetic patients.

To examine the mechanisms of hyperglycemia-induced insulin resistance, eight insulin-dependent (type I) diabetic men were studied twice, after 24 h of hyperglycemia (mean blood glucose 20.0 +/- 0.3 mM, i.v. glucose) and after 24 h of normoglycemia (7.1 +/- 0.4 mM, saline) while receiving identical diets and insulin doses. Whole-body and forearm glucose uptake were determined during a 300-min insulin infusion (serum free insulin 359 +/- 22 and 373 +/- 29 pM, after hyper- and normoglycemia, respectively). Muscle biopsies were taken before and at the end of the 300-min insulin infusion. Plasma glucose levels were maintained constant during the 300-min period by keeping glucose for 150 min at 16.7 +/- 0.1 mM after 24-h hyperglycemia and increasing it to 16.5 +/- 0.1 mM after normoglycemia and by allowing it thereafter to decrease in both studies to normoglycemia. During the normoglycemic period (240-300 min), total glucose uptake (25.0 +/- 2.8 vs. 33.8 +/- 3.9 mumol.kg-1 body wt.min-1, P less than 0.05) was 26% lower, forearm glucose uptake (11 +/- 4 vs. 18 +/- 3 mumol.kg-1 forearm.min-1, P less than 0.05) was 35% lower, and nonoxidative glucose disposal (8.9 +/- 2.2 vs. 19.4 +/- 3.3 mumol.kg-1 body wt-1min-1, P less than 0.01) was 54% lower after 24 h of hyper- and normoglycemia, respectively. Glucose oxidation rates were similar. Basal muscle glycogen content was similar after 24 h of hyperglycemia (234 +/- 23 mmol/kg dry muscle) and normoglycemia (238 +/- 22 mmol/kg dry muscle). Insulin increased muscle glycogen to 273 +/- 22 mmol/kg dry muscle after 24 h of hyperglycemia and to 296 +/- 33 mmol/kg dry muscle after normoglycemia (P less than 0.05 vs. 0 min for both). Muscle ATP, free glucose, glucose-6-phosphate, and fructose-6-phosphate concentrations were similar after both 24-h treatment periods and did not change in response to insulin. We conclude that a marked decrease in whole-body, muscle, and nonoxidative glucose disposal can be induced by hyperglycemia alone.     

Humalog Mix25 improves 24-hour plasma glucose profiles compared with the human insulin mixture 30/70 in patients with type 2 diabetes mellitus.

OBJECTIVE: To compare the effects of Humalog Mix25 (Humalog Mix75/25 in the USA) (Mix25) and human insulin 30/70 (30/70) on the 24-hour inpatient plasma glucose (PG) profile in patients with type 2 diabetes mellitus (T2DM). DESIGN: A randomised, open-label, 8-week crossover study. Study insulins were injected twice daily, 5 minutes before breakfast and dinner. SETTING: Four-week outpatient (dose-adjustment) treatment phase, and 3-day inpatient (test) phase. PATIENTS: Twenty-five insulin-treated patients with T2DM (ages 40-66 years), mean (+/- standard error of the mean) (SEM) HbA1c 7.7% +/- 0.23%, and body mass index (BMI) 29.3 +/- 0.83 kg/m2. OUTCOME MEASURES: 24-hour PG profiles, PG excursions after meals, PG area under the curve (AUC), and 30-day hypoglycaemia rate. RESULTS: The 2-hour PG excursions following breakfast (5.5 +/- 0.34 v. 7.2 +/- 0.34 mmol/l, p = 0.002) and dinner (2.4 +/- 0.27 v. 3.4 +/- 0.27 mmol/l, p = 0.018) were smaller with Mix25 than with 30/70. PG AUC between breakfast and lunch was smaller with Mix25 than with 30/70 (77.6 +/- 3.8 v. 89.5 +/- 4.3 mmol/h/ml, p = 0.001). PG AUC between lunch and dinner, dinner and bedtime, and bedtime and breakfast did not differ between treatments. Pre-meal and nocturnal PG were comparable. The postprandial insulin requirement for lunch meals was supplied equally by the two insulin treatments. The thirty-day hypoglycaemia rate was low (Mix25 0.049 +/- 0.018 v. 30/70 0.100 +/- 0.018 episodes/patient/30 days, p = 0.586) for both treatments. CONCLUSION: In patients with T2DM, Mix25 improved the 24-hour PG profile with lower postprandial PG excursions than with human insulin 30/70.     

Evaluation of the effect of gain on the meal response of an automated closed-loop insulin delivery system

A continuous closed-loop insulin delivery system using subcutaneous insulin delivery was evaluated in eight diabetic canines. Continuous glucose profiles were obtained by extrapolation of blood glucose measurements. Insulin delivery rate was calculated, using a model of beta-cell insulin secretion, and delivered with a Medtronic MiniMed subcutaneous infusion pump. The model acts like a classic proportional-integral-derivative controller, delivering insulin in proportion to glucose above target, history of past glucose values, and glucose rate of change. For each dog, a proportional gain was set relative to the open-loop total daily dose (TDD) of insulin. Additional gains based on 0.5 x TDD and 1.5 x TDD were also evaluated (gain dose response). Control was initiated 4 h before the meal with a target of 6.7 mmol/l. At the time of the meal, glucose was similar for all three gains (6.0 +/- 0.3, 5.2 +/- 0.3, and 4.9 +/- 0.5 mmol/l for 0.5 x TDD, TDD, and 1.5 x TDD, respectively; P > 0.05) with near-target values restored at the end of experiments (8.2 +/- 0.9, 6.0 +/- 0.6, and 6.0 +/- 0.5, respectively). The peak postprandial glucose level decreased significantly with increasing gain (12.1 +/- 0.6, 9.6 +/- 1.0, and 8.5 +/- 0.6 mmol/l, respectively; P < 0.05). The data demonstrate that closed-loop insulin delivery using the subcutaneous site can provide stable glycemic control within a range of gain.     

Captopril once daily in patients with essential hypertension and hyperuricaemia

Captopril (Capoten; Squibb) 100 mg was given as once-daily monotherapy in 20 patients with hypertension and hyperuricaemia. Ten patients (group A) maintained a low-sodium diet (60-100 mmol/d) throughout the study and 10 (group B) continued their usual high-sodium (200-300 mmol/d) diet. After 4 weeks of active treatment supine blood pressure in group A decreased from 192 +/- 5/119 +/- 3 mmHg to 144 +/- 3/95 +/- 3 mmHg (P less than 0,001), whereas pressures in group B varied between 168 +/- 5/115 +/- 3 mmHg and 160 +/- 6/113 +/- 4 mmHg (not significant). Serum urate values fell from 0,46 +/- 0,02 mmol/l to 0,35 +/- 0,02 mmol/l (P less than 0,001) and 0,53 +/- 0,02 mmol/l to 0,46 +/- 0,03 mmol/l (P less than 0,05) in the same groups. Captopril exerted an antihypertensive effect in patients receiving a low-sodium diet, suggesting a relationship with angiotensin II and/or aldosterone; effects on serum urate levels appeared to be independent of diet.     

Regulation of whole-body leucine metabolism with insulin during mixed-meal absorption in normal and diabetic humans

To determine the effects of insulin on dietary and endogenous leucine metabolism, five normal subjects, seven insulin-insufficient insulin-dependent (IDDM) diabetic patients, and five diabetic patients controlled with continuous subcutaneous insulin infusion (CSII) were studied before and for 8 h after ingestion of a chemically defined elemental test meal (10 cal/kg) containing crystalline amino acids. L-[1-14C]leucine was included in the meal to trace the entry and oxidation of the dietary leucine. Total (meal + endogenous) entry of leucine into the circulation was estimated with a constant infusion of [2H3]leucine. Postabsorptive and meal-related increases in the plasma leucine concentration were greater (P less than .05) in the insulin-insufficient IDDM than in the normal subjects but returned to near-normal values with CSII. Baseline leucine flux was approximately 40% greater in the insulin-insufficient IDDM than in normal subjects (2.17 +/- 0.17 vs. 1.55 +/- 0.15 mumol.kg-1.min-1, respectively; .05 less than P less than .01) but were near normal during CSII treatment (1.85 +/- 0.25 mumol.kg-1.min-1). Furthermore, total leucine entry during meal absorption was greater in the insulin-insufficient IDDM (1.41 +/- 0.10 mmol.kg-1.8 h-1) than in either normal (0.96 +/- 0.08 mmol.kg-1.8 h-1, P less than .01) or IDDM subjects during CSII treatment (1.09 +/- 0.11 mmol.kg-1.8 h-1, P less than .05). Fractional oxidation (approximately 40-50%) and entry of dietary leucine were similar in all three groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transient stimulatory effect of sustained hyperglucagonemia on splanchnic glucose production in normal and diabetic man.

Insulin can modulate glucagon-stimulated hepatic glucose production and is considered to be the major factor acting in vivo to exert a couterregulatory action to glucagon. The insulin-dependent diabetic, therefore, might be especially vulnerable to enhanced hepatic glucose production promoted by glucagon. To investigate this hypothesis, low-dose glucagon infusions were administered to normal and diabetic men to compare the effects of glucagon on net splanchnic glucose production (NSGP). Four normal and three insulin-dependent, ketosis-prone, hyperglycemic diabetic men (insulin withheld for 24 hours) underwent brachial-artery-hepatic-vein catheterization. Each received a 90-minute glucagon infusion at 5 ng/kg./min. Glucagon levels rose four-to-fivefold in both groups, plateauing at 300-600 pg./ml. In the normals, NSGP rose from 92+/-12 to 211+/-31 mg./min. at 15 minutes and returned to basal levels by 45 minutes. Insulin measured in the hepatic vein rose from 19+/-6 to 33+/-11 muU/.ml., while plasma glucose rose 17 mg./dl. In the insulin-dependent diabetics, NSGP rose from 78+/-24 to a peak of 221+/-33 mg./min. at 30 minutes and then fell sharply to 113+/-15 mg./min. at 60 minutes despite continuing hyperglucagonemia. Plasma glucose in the diabetics rose 21 mg./dl. These data suggest a mechanism that acts to rapidly diminish glucagon-induced hepatic glucose production in diabetic man but does not appear to be mediated by increased insulin secretion.     

Muscle glucose uptake is effectively activated by ischemia in type 2 diabetic subjects

It has previously been shown that Wortmannin, a phosphatidylinositol 3-kinase inhibitor, inhibits glucose transport activated by insulin but not by ischemia, suggesting the importance of an activating mechanism that bypasses the insulin signal. To evaluate the relevance of this insulin-independent pathway in insulin-resistant subjects, the ability of ischemia to stimulate glucose uptake was investigated in 9 patients with type 2 diabetes and in 9 healthy control subjects (fasting glucose level 9.4 +/- 0.8 vs. 5.1 +/- 0.1 mmol/l, P < 0.001, in type 2 diabetic patients and control subjects, respectively; fasting insulin level insulin 8.1 +/- 2.6 vs. 4.5 +/-0.7 mU/l, P < 0.05, respectively) matched for sex, age, and BMI. Arterial plasma and interstitial concentrations of glucose and lactate (measured by subcutaneous and muscle microdialysis) were recorded in the forearm before, during, and after ischemia induced locally for 20 min. During ischemia, the muscle interstitial glucose concentration decreased significantly from 7.7 +/- 0.6 to 5.4 +/- 0.4 mmol/l (P < 0.01) and from 4.4 +/- 0.3 to 3.6 +/- 0.3 mmol/l (P < 0.05) in type 2 diabetic patients and control subjects, respectively. The arterial-interstitial (A-I) glucose concentration difference was 1.7 +/- 0.6 and 0.7 +/- 0.3 mmol/ at basal, and it increased significantly to 3.5 +/- 0.7 (P < 0.01) and 1.4 +/-0.3 mmol/l (P < 0.05) during ischemia in each group, respectively. Interstitial lactate increased significantly during ischemia from 0.8 +/- 0.1 to 1.1 +/- 0.1 mmol/l (P < 0.05) and from 0.5 +/- 0.1 to 0.9 +/- 0.2 mmol/l (P < 0.05), respectively. The A-I glucose concentration difference was abolished immediately postischemia and regained after approximately 15 min, whereas high interstitial lactate levels remained elevated throughout the study. Subcutaneous interstitial glucose concentrations remained unchanged during ischemia and postischemia in both groups, whereas the interstitial lactate concentration in adipose tissue increased during ischemia from 1.4 +/- 0.2 to 2.0 +/- 0.2 mmol/l (P < 0.05) and from 1.1 +/- 0.1 to 1.8 +/- 0.3 mmol/l (P < 0.05) in type 2 diabetic patients and control subjects, respectively. Plasma glucose and lactate levels were unchanged in both groups during the study period. The results show that in muscle, but not in adipose tissue, glucose uptake is efficiently activated by ischemia in insulin-resistant type 2 diabetic subjects, suggesting the activation of a putative alternative pathway to the insulin signal in muscle cells.     

Effects of long-term optimization and short-term deterioration of glycemic control on glucose counterregulation in type I diabetes mellitus

To assess the effects of glycemic control on glucose counterregulation, rates of plasma glucose recovery from hypoglycemia and counterregulatory hormonal responses were studied in 18 C-peptide-negative patients with insulin-dependent diabetes mellitus (IDDM) before and after either improvement, no change, or deterioration in glycemic control. Hypoglycemia was induced by an i.v. insulin infusion (30 mU/m2 X min for 1 h) after maintenance of euglycemia overnight with i.v. insulin. In 13 patients with long duration of IDDM (9 +/- 0.5 yr, mean +/- SEM) and initially poor glycemic control (mean diurnal blood glucose, MBG 199 +/- 8 mg/dl, ketoamine-HbA1 12.4 +/- 0.2%; nondiabetic subjects 104 +/- 4 mg/dl and 6.8 +/- 0.09%, respectively), rates of plasma glucose recovery from hypoglycemia (0.30 +/- 0.01 versus 0.60 +/- 0.01 mg/dl X min in nondiabetic subjects, P less than 0.001) and plasma glucagon (AUC 0.56 +/- 0.09 versus 6.3 +/- 0.50 ng/ml X 150 min in nondiabetic subjects, P less than 0.01) and epinephrine (AUC 16.9 +/- 0.2 versus 25.7 +/- 0.2 ng/ml X 150 min in nondiabetic subjects, P less than 0.001) responses to hypoglycemia were impaired. Intensive therapy (three daily injections of insulin) instituted in 7 out of 13 IDDM patients for up to 9 mo improved MBG (124 +/- 6 mg/dl, P less than 0.01) and ketoamine-HbA1 (7.9 +/- 0.02%, P less than 0.01) but not rates of plasma glucose recovery (0.31 +/- 0.01 mg/dl X min) and plasma glucagon (AUC 0.69 +/- 0.07 ng/ml X 150 min) and epinephrine (AUC 14.9 +/- 0.17 ng/ml X 150 min) responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Maintenance of normoglycemia during cardiac surgery

We used the hyperinsulinemic normoglycemic clamp technique, i.e., infusion of insulin at a constant rate combined with dextrose titrated to clamp blood glucose at a specific level, to preserve normoglycemia during elective cardiac surgery. Ten nondiabetic and seven diabetic patients entered the clamp protocols. Perioperative glucose control was also assessed in 19 nondiabetic and 11 diabetic patients (control group) receiving a conventional insulin infusion sliding scale. In patients of the clamp group, a priming bolus of insulin (2 U) was started before the induction of anesthesia followed by infusions of insulin at 5 mU. kg(-1). min(-1) and of variable amounts of dextrose. Arterial blood glucose was measured every 5 min in the clamp group and every 20 min in the control group. Control of normoglycemia was defined as > or =95% of the glucose levels within 4.0-6.0 mmol/L. Glucose concentration was recorded before surgery, 15 min before cardiopulmonary bypass (CPB), during early and late CPB, and at sternal closure. Patients of the control group became progressively hyperglycemic during surgery (late CPB; nondiabetics, 9.0 +/- 3.2 mmol/L; diabetics, 10.1 +/- 3.6 mmol/L), whereas normoglycemia was achieved in the study group (late CPB; nondiabetics, 5.5 +/- 0.7 mmol/L; diabetics, 4.9 +/- 0.6 mmol/L; P < 0.05 versus control group). In conclusion, it seems that normal blood glucose concentration during open heart surgery can be reliably maintained in nondiabetic and diabetic patients by using the hyperinsulinemic normoglycemic clamp technique.     

Increased peripheral insulin sensitivity and muscle mitochondrial enzymes but unchanged blood glucose control in type I diabetics after physical training

Nine male, insulin-dependent diabetic patients participated in a 16-wk training program consisting of 1 h of jogging, running, ball games, and gymnastics, performed 2-3 times/wk. The training resulted in an 8% increase of maximal oxygen uptake (P less than 0.01). Insulin sensitivity as determined by the insulin clamp technique increased 20% (P less than 0.05). Glycosylated hemoglobin showed no change (10.4 +/- 0.7% versus 11.3 +/- 0.5%), 24-h urinary glucose excretion was not reduced, and home-monitored urine tests were unchanged. The frequency of hypoglycemic attacks did not change during the training period and body weight remained constant. There was a 14% fall in plasma cholesterol (P less than 0.01) and a rise in the proportion of HDL-cholesterol from 24 +/- 2% to 30 +/- 3% (P less than 0.01). Thigh muscle oxidative capacity increased, as indicated by a 24% increase in succinate dehydrogenase activity (P less than 0.05). The number of capillaries/muscle fiber increased 15% (P less than 0.01). However, as the mean muscle fiber cross-sectional area increased to a similar extent (11%, P less than 0.05), capillary density (cap x mm-2) was unchanged. In conclusion, this study demonstrates that physical training in insulin-dependent diabetics results in increased peripheral insulin sensitivity, a rise in muscle mitochondrial enzyme activities, decreased total plasma cholesterol levels, and unchanged blood glucose control. The findings suggest that in the absence of efforts to alter dietary regulation and insulin administration, physical training consisting of 2-3 weekly bouts of moderate exercise may not of itself improve blood glucose control in type I diabetes.     

Glucose-dependent insulinotropic polypeptide augmentation of insulin. Physiology or pharmacology?

Glucose-dependent insulinotropic polypeptide (GIP) is said to be a major physiologic factor in the augmentation of the insulin response to oral glucose. Whether GIP promotes insulin release at physiologic concentrations of glucose or GIP, however, is questionable. To investigate this further, volunteers were infused with 10, 20, or 40 g intravenous (i.v.) glucose, with or without simultaneous GIP infusion, to produce plasma levels of GIP or glucose similar to those seen after oral glucose. The effect of 40 g i.v. glucose with three times the original dose of GIP was also investigated. No significant enhancement of glucose-stimulated insulin secretion was seen when GIP was infused with 10 or 20 g i.v. glucose; however, with 40 g a doubling of the insulin response occurred. The higher dose of GIP caused a further increase in insulin response (30-min increment, 972 +/- 191 pmol/L; compared with glucose alone, 356 +/- 100 pmol/L, P less than 0.01; and compared with low GIP, 602 +/- 247 pmol/L, P less than 0.02). The glucose increment after the 40-g i.v. dose was +9.2 mmol/L. The concentration of GIP and glucose required to produce significant potentiation of the insulin response appears to be in the pharmacologic, rather than physiologic, range.     

Efficacy of octreotide acetate in treatment of severe postgastrectomy dumping syndrome.

The present study evaluates the acute and chronic use of a long-acting somatostatin analog, octreotide acetate, in the treatment of patients with severe postgastrectomy dumping syndrome. In the acute phase, 10 patients with severe dumping were studied over 2 consecutive days before and for 3 hours after the ingestion of a 'dumping breakfast' in a randomized double-blind fashion. On one day octreotide (100 micrograms) was given subcutaneously 30 minutes before the test meal and on the other day an equal volume of vehicle was injected. An additional group of six postgastrectomy patients without dumping were studied in a similar fashion and these acted as controls. During placebo treatment the test meal resulted in an immediate increase (p less than 0.01) in the pulse rate and in plasma levels of glucose, glucagon, pancreatic polypeptide, neurotensin, and insulin. Similar changes were seen in the control group with respect to placebo; however glucagon and neurotensin (p less than 0.05) did not show the same magnitude of increase as seen with placebo. Treatment with octreotide acetate prevented the development of both vasomotor and gastrointestinal symptoms and completely ablated all of the above responses in plasma peptides. These changes were associated with complete ablation of diarrhea (p less than 0.001). Pretreatment with octreotide acetate completely suppressed the rise in plasma insulin response to the meal and this ablated the late hypoglycemia of dumping. Treatment with octreotide acetate resulted in delayed gastric emptying and transit time (578 +/- 244 minutes) versus 76 +/- 23 minutes with placebo and 125 +/- 36 minutes in controls (p less than 0.05). Chronic daily treatment with octreotide acetate resulted in minimal side effects. These patients demonstrated a stable fasting plasma glucose, normal liver function tests, and an average weight gain of 11% during a 12-month period. In addition most patients were able to resume employment. The long-acting somatostatin analog, octreotide acetate, is highly effective in preventing the development of symptoms of severe dumping syndrome, both vasomotor and gastrointestinal.     

Effects of the sulphonylurea drugs gliclazide and glibenclamide on blood glucose control and platelet function.

Platelet aggregation and adhesion are commonly increased in diabetes mellitus. These abnormalities may in part be responsible for the increased incidence of vascular disease in diabetics. We have investigated the effects of diet, diet plus glibenclamide, and diet plus gliclazide on plasma glucose control and platelet function in 10 newly diagnosed maturity-onset diabetics who had not previously been treated. Before treatment, the mean postprandial plasma glucose value was 13,4 +/- 0,8 mmol/l, which fell insignificantly on dietary treatment, to 12,2 +/- 1,0 mmol/l (P greater than 0,05). Both glibenclamide and gliclazide, when added to the diet, significantly lowered mean plasma glucose values to 9,3 +/- 0,8 mmol/l and 7,8 +/- 0,8 mmol/l respectively (P less than 0,05). Platelet aggregation in response to 1 mumol adenosine diphosphate (ADP) was increased in the diet period, whereas aggregation in response to 10 mumol and 100 mumol was normal. This suggests an increased sensitivity of the platelets to ADP in diabetic patients. The addition of both glibenclamide and gliclazide reduced the magnitude of the response to within the normal range. Platelet aggregation in response to 10 mumol adrenaline and 750 micrograms/ml collagen was significantly reduced by glibenclamide (P less than 0,05). We conclude that sulphonylurea therapy appears to reduce the increased platelet aggregation which occurs in diabetics. This may play a role in the prevention of vascular disease.     

Assessing insulin secretion by modeling in multiple-meal tests: role of potentiation

We developed a mathematical model of the glucose control of insulin secretion capable of quantifying beta-cell function from a physiological meal test. The model includes a static control, i.e., a secretion component that is a function of plasma glucose concentration (the dose-response function), and a dynamic control, i.e., a secretion component that is proportional to the positive values of the glucose concentration derivative. Furthermore, the dose-response function is assumed to be modulated by a time-varying potentiation factor. To test the model, nine nondiabetic control subjects and nine type 2 diabetic patients received three standardized mixed meals over a period of 14-15 h. Blood samples were drawn for the measurement of glucose, insulin, and C-peptide concentration. The dose-response function, the parameter of the dynamic control, and the potentiation factor were determined by fitting the model to glucose and C-peptide concentrations. In diabetic patients, the dose-response function was shifted to the right (glucose concentration at a reference insulin secretion of 300 pmol.min(-1).m(-2) was 11.7 +/- 1.1 vs. 7.2 +/- 0.7 mmol/l; P < 0.05), and decreased in slope (53 +/- 15 vs. 148 +/- 38 pmol.min(-1).m(-2).mmol(-1).l; P < 0.05) and the parameter of the dynamic control was decreased (220 +/- 67 vs. 908 +/- 276 pmol.m(-2).mmol(-1).l; P < 0.05) compared with the nondiabetic control subjects. Furthermore, potentiation was markedly blunted and delayed: maximum potentiation was observed at the first meal in normal subjects and at the second meal (about 4 h later) in diabetic subjects; the mean time for the potentiation factor was higher (7.1 +/- 0.2 vs. 5.9 +/- 0.2 h; P < 0.01), and the size of potentiation was reduced (2.6 +/- 0.5 vs. 7.2 +/- 1.5 fold increase; P < 0.005). In conclusion, our model of insulin secretion extracts multiple indexes of beta-cell function from a physiological meal test. Use of the model in patients with type 2 diabetes retrieves known defects in insulin secretion but also uncovers new facets of beta-cell dysfunction.     

Neural regulation of pancreatic polypeptide release

To clarify the nervous system's role in the regulation of pancreatic polypeptide (PP) release, extrinsic innervation to the in situ pancreas was eliminated in five dogs. Before and 2 weeks after denervation, PP was measured during insulin hypoglycemia and ingestion of a protein meal. Exogenous insulin caused a similar marked hypoglycemia in both control and denervated dogs. Hypoglycemia caused a significant increase in plasma PP in control dogs from a baseline of 42 +/- 8 pg/ml to 86 +/- 18 pg/ml at 20 minutes (P less than 0.01). In denervated dogs plasma PP did not increase with hypoglycemia, and levels were significantly less than in the control animals at 30 and 60 minutes (P less than 0.05). With a protein meal, PP increased in the control animals from 53 +/- 12 to 116 +/- 16 pg/ml at 10 minutes (P less than 0.05), 164 +/- 22 pg/ml at 20 minutes (P less than 0.05), and 193 +/- 20 pg/ml at 60 minutes (P less than 0.01). Denervation markedly blunted this response, and PP increased only from 53 +/- 6 to 64 +/- 4 pg/ml at 10 minutes, to 83 +/- 12 pg/ml at 20 minutes, and to 91 +/- 8 pg/ml at 60 minutes. PP became significantly elevated above baseline in denervated dogs only at 60 minutes (P less than 0.05), and PP was significantly lower than in the control group at 10, 20, and 60 minutes after the meal (P less than 0.05). Immunostaining for insulin, glucagon, somatostatin, and PP showed no difference in the number and distribution of these endocrine cells in predenervation and postdenervation specimens. Adrenergic and cholinergic nerves were seen in all control specimens but, except for a few adrenergic fibers, were not seen in denervated animals. Peptidergic nerves that contained vasoactive intestinal polypeptide (VIP) were seen in all areas of the pancreas before and after denervation. This study confirms that the initial rise in PP with a protein meal is governed by vagal cholinergic pathways. Later postprandial PP secretion is controlled by an interplay between these cholinergic pathways and other uncertain influences such as hormonal or substrate changes. The pancreas has a rich intrinsic peptidergic system of VIP-containing nerves.     

Treatment of hyperkalaemia in renal failure: salbutamol v. insulin

Three groups of patients with acute or chronic renal failure (GFR less than 5 ml/min) and hyperkalaemia (K+ greater than or equal to 6 mEq/l), similar in age, serum creatinine and pretreatment K+. Group A (n = 24) received salbutamol 0.5 mg i.v. in 15 min, group B (n = 10) received glucose 40 g i.v. plus 10 units insulin i.v. in 15 min, and group C (n = 10) received salbutamol 0.5 mg i.v., glucose 40 g i.v. and insulin 10 units i.v. over a 15-min period. Serum potassium was measured at 30, 60, 180 and 360 min after administration of treatment. All treatments reduced serum potassium, maximal at 30 or 60 min, and ranging from -0.5 +/- 0.1 to -1.5 +/- 0.2 mEq/l; patients in group C exhibited a significantly greater decrement in serum potassium, when compared to group B at 60 (-1.5 +/- 0.2 vs -1 +/- 0.1 mEq/l, respectively; P less than 0.01) and 180 min (-1.2 +/- 0.2 vs -0.7 +/- 0.1 mEq/l, respectively; P less than 0.05). There were no significant differences between groups A and C. Patients from group C had moderate tachycardia and more prolonged hyperglycaemia than those from group B, but all treatments were well tolerated.     

Effect of cisapride on delayed gastric emptying in diabetic patients

Delayed gastric emptying is supposed to affect glycemic control in diabetic patients by relative over dosing of insulin to blood glucose level due to delayed absorption of nutrients. Therefore, treatment of delayed gastric emptying is important in diabetic patients. Cisapride, a potent gastrokinetic agents, has been reported to activate the motility from stomach to colon. We evaluated the effect of acute oral administration of cisapride in seven diabetic patients (aged 46-62) with delayed gastric emptying. All patients complicated with autonomic neuropathy. Ten mg of cisapride was administered orally 30 minutes before breakfast and lunch on the day of study. Gastric emptying study was done using 99mTc-tin colloid labeled omelet meal served with 2 slices of toast and 200 ml of milk. With cisapride, the retention rate at time of 150 minutes decreased from 76 +/- 10% to 47 +/- 13% (mean +/- SD) (p less than 0.001) and starting index shortened from 86 +/- 28 minutes to 38 +/- 27 minutes (p less than 0.05). Gastric emptying speed became faster from 0.31 +/- 0.16%/min to 0.43 +/- 0.12%/min (0.2 greater than p greater than 0.1). Blood glucose level before meal decreased from 117 +/- 27 mg/dl (mean +/- SE) to 74 +/- 7 mg/dl (n.s.), and difference between basal and maximal blood glucose level became larger from 46 +/- 27 mg/dl to 84 +/- 30 mg/dl (n.s.). We conclude that acute oral administration of cisapride has significant effect in improving delayed emptying of solid meal in diabetic patients.     

The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia

We studied the mechanisms and physiological relevance of the cephalic insulin response to meal ingestion in 12 healthy women (age 63 +/- 0.4 years; BMI 27.7 +/- 1.7 kg/m2). The ganglionic antagonist, trimethaphan, which impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia, or atropine or saline was given intravenously during the first 15 min after ingestion of a standard meal (350 kcal). During saline infusion, insulin levels increased during the first 10 min after meal ingestion, whereas the first increase in glucose was evident at 15 min. The preabsorptive 10-min insulin response was reduced by 73 +/- 11% by trimethaphan (P = 0.009), accompanied by impaired reduction of glucose levels from 25 to 60 min after meal ingestion (deltaglucose = -1.27 +/- 0.5 [with saline] vs. 0.1 +/- 0.4 mmol/l [with trimethaphan]; P = 0.008). This reduction at 25-60 min in glucose levels correlated significantly to the 10-min insulin response (r = 0.65, P = 0.024). The 10-min insulin response to meal ingestion was also reduced by atropine, but only by 20 +/- 9% (P = 0.045), which was lower than the reduction with trimethaphan (P = 0.004). The preabsorptive insulin response was not accompanied by any increase in circulating levels of gastric inhibitory polypeptide (GIP) or glucagon-like peptide 1 (GLP-1). In conclusion, 1) the early preabsorptive insulin response to meal ingestion in humans can be largely attributed to autonomic activation mediated by noncholinergic and cholinergic mechanisms, 2) this cephalic insulin response is required for a normal postprandial glucose tolerance, and 3) GIP and GLP-1 do not contribute to the preabsorptive cephalic phase insulin response to meal ingestion.     

Insulin infusion (GIK) in the treatment of type 2 (non-insulin dependent) diabetes during the perioperative period

The effect of surgery on intermediary metabolism has been studied in six non-diabetic subjects, eleven type 2 diabetic subjects untreated during surgery, and nine type 2 diabetic subjects treated by glucose-insulin-potassium (GIK) infusion during surgery. Plasma glucose results were studied in all subjects and other metabolites whenever possible. Initial glucose concentrations were similar in both groups of diabetic subjects. Four hours postoperatively the plasma glucose was lower in the GIK group (10.1 +/- 1.0 mmol/l) than in untreated subjects (14.2 +/- 1.3 mmol/l, P less than 0.05) but still far above levels found in non-diabetic subjects. Lactate concentration was higher in the GIK treated diabetic subjects than in both non-GIK treated diabetic and non-diabetic patients 15 min after induction (1.32 +/- 0.07 compared with 0.93 +/- 0.09 and 0.89 +/- 0.08 mmol/l, P less than 0.02). Non-esterified fatty acid (NEFA) was lower one hour postoperatively in the GIK treated diabetic group than in the non-GIK diabetic patients (0.47 +/- 0.09 mmol/l compared with 1.09 +/- 0.22 mmol/l, P less than 0.05). All NEFA concentrations were lower in GIK treated diabetic subjects than in non-diabetic subjects for the time of insulin infusion. Blood 3-hydroxybutyrate was also lower in GIK treated (0.04 +/- 0.02) than in untreated diabetic subjects 4 h postoperatively (0.25 +/- 0.07 mmol/l, P less than 0.05). The levels of non-esterified fatty acid and 3-hydroxybutyrate found in the untreated diabetic did not differ from those found in non-diabetic controls. Plasma cortisol levels had risen in all groups 4 h postoperatively (P less than 0.01).