Biomedical subjects

F Q Nuttall

Publications and source records attributed to F Q Nuttall.

At least 19 recordsLinked to original sources

PubMed2006

Effect of orally administered phenylalanine with and without glucose on insulin, glucagon and glucose concentrations.

OBJECTIVE: As part of our studies of the metabolic effects of ingested proteins, we are currently investigating the effects of ingestion of individual amino acids. The objective of the present study was to determine whether ingested phenylalanine stimulates insulin and/or glucagon secretion, and if phenylalanine ingested with glucose modifies the insulin, glucagon or glucose response to the ingested glucose. DESIGN: Six healthy subjects were tested on 4 separate occasions. Plasma phenylalanine, glucose, insulin, glucagon, and total alpha amino nitrogen (AAN) (i.e., total amino acids) concentrations were measured at various times during a 2.5 h period after ingestion of 1 mmol phenylalanine/kg lean body mass, 25 g glucose, 1 mmol phenylalanine/kg lean body mass+25 g glucose, or water only, given in random order. RESULTS: Following phenylalanine ingestion, the circulating phenylalanine concentration increased approximately 14 fold and remained elevated for the duration of the experiment. Glucagon and AAN increased, insulin increased modestly, and glucose was unchanged when compared to water ingestion. When glucose was ingested with phenylalanine, the circulating phenylalanine, glucagon, AAN, and insulin area responses were approximately the sum of the responses to phenylalanine alone and glucose alone. However, the plasma glucose area response was decreased 66% when phenylalanine was co-ingested with glucose. CONCLUSION: In summary, phenylalanine in an amount moderately greater than that in a large protein meal stimulates an increase in insulin and glucagon concentration. It markedly attenuates the glucose-induced rise in plasma glucose when ingested with glucose.

Administration, Oral↗

PubMed2001

Glucose appearance rate after the ingestion of galactose.

Galactose is one of the monosaccharides of importance in human nutrition. It is converted to glucose-1-phosphate in the liver and subsequently stored as glycogen, or is converted to glucose and released into the circulation. The increase in plasma glucose is known to be modest following galactose ingestion. Whether this is due to a small increase in hepatic glucose output, or to a relatively large increase in hepatic glucose output but a concomitant increase in glucose disposal, is not known in humans. Therefore, the rates of glucose appearance (Ra) and disappearance (Rd) were determined over an 8-hour period in normal subjects using an isotope dilution technique. The subjects ingested 50 g galactose or water alone in random order at 8 AM on separate occasions. Plasma glucose, glucagon, lactate, urea nitrogen, total amino acids, and uric acid and serum insulin and triglycerides also were determined. Following galactose ingestion, there was a modest transient increase in peripheral glucose and insulin concentrations. This was associated with a modest increase in the glucose Ra. The calculated amount of glucose appearing in the circulation as a result of galactose ingestion was 9.8 g, while the amount of glucose disappearing over the 8 hours was 9.9 g. Thus, following ingestion of 50 g galactose by overnight-fasted men, approximately 20% appears as additional glucose in the circulation. Data obtained in animals suggest that a large amount of the galactose is stored as glucose in glycogen. Nevertheless, the conversion of galactose to glucose in the liver may have been greater than suggested by the increase in glucose appearance in the circulation due to substitution for other gluconeogenic substrates.

Adult↗

PubMed2001

Uric acid inhibits liver phosphorylase a activity under simulated in vivo conditions.

We have reported that glycogen synthesis and degradation can occur in vivo without a significant change in the amount of phosphorylase a present. These data suggest the presence of a regulatable mechanism for inhibiting phosphorylase a activity in vivo. Several effectors have been described. AMP stimulates, whereas ADP, ATP, and glucose inhibit activity. Of these effectors, only the glucose concentration changes under normal conditions; thus it could regulate phosphorylase a activity in vivo. We previously have reported that, when all of these effectors were present at physiological concentrations, the net effect was no change in phosphorylase a activity. Addition of caffeine, an independent inhibitor of activity, to the above effectors not only resulted in inhibition but also restored a glucose concentration-dependent inhibition. Because uric acid is an endogenous xanthine derivative, we decided to determine whether it had an effect on phosphorylase a activity. Independently, uric acid did not affect activity; however, when added at a presumed physiological concentration in combination with AMP, ADP, ATP, and glucose, it inhibited activity. A modest but not statistically significant glucose concentration-dependent inhibition was also present. Thus uric acid may play an important role in regulating phosphorylase a activity in vivo.

Adenine Nucleotides↗

PubMed2001

Effect of protein ingestion on the glucose appearance rate in people with type 2 diabetes.

Amino acids derived from ingested protein are potential substrates for gluconeogenesis. However, several laboratories have reported that protein ingestion does not result in an increase in the circulating glucose concentration in people with or without type 2 diabetes. The reason for this has remained unclear. In people without diabetes it seems to be due to less glucose being produced and entering the circulation than the calculated theoretical amount. Therefore, we were interested in determining whether this also was the case in people with type 2 diabetes. Ten male subjects with untreated type 2 diabetes were given, in random sequence, 50 g protein in the form of very lean beef or only water at 0800 h and studied over the subsequent 8 h. Protein ingestion resulted in an increase in circulating insulin, C-peptide, glucagon, alpha amino and urea nitrogen, and triglycerides; a decrease in nonesterified fatty acids; and a modest increase in respiratory quotient. The total amount of protein deaminated and the amino groups incorporated into urea was calculated to be approximately 20-23 g. The net amount of glucose estimated to be produced, based on the quantity of amino acids deaminated, was approximately 11-13 g. However, the amount of glucose appearing in the circulation was only approximately 2 g. The peripheral plasma glucose concentration decreased by approximately 1 mM after ingestion of either protein or water, confirming that ingested protein does not result in a net increase in glucose concentration, and results in only a modest increase in the rate of glucose disappearance.

Adult↗

PubMed2000

Heterogeneity in Paget disease of the bone.

Paget disease of the bone is a common skeletal disorder. Recently, a gene for Paget disease was localized to 18q with subsequent evidence for linkage heterogeneity. We report the identification and clinical characterization of a large pedigree of Paget disease and demonstrate that the Paget disease gene in this pedigree is not linked to the region on 18q, thus confirming linkage heterogeneity.

Adult↗

PubMed2000

Peripheral glucose appearance rate following fructose ingestion in normal subjects.

Ingested fructose is rapidly utilized by the liver and is either stored as glycogen, converted to glucose, or oxidized to CO2 for energy. The glycemic response to fructose is known to be modest. However, the relative importance of these pathways in humans is unclear. In the present study, a tritiated glucose tracer dilution technique was used to determine the effect of fructose ingestion on the glucose appearance rate (Ra) in the peripheral circulation over an 8-hour period beginning at 8:00 AM. Six normal healthy males ingested 50 g fructose with 500 mL water. On a separate occasion, the same subjects received 500 mL water without fructose as a control. Serum insulin, triglycerides, plasma glucagon, glucose, lactate, alanine, urea nitrogen, and total amino acids also were determined. The plasma glucose concentration was not significantly different following ingestion of fructose or water, other than a transient increase beginning at 8:30 AM of 0.8 mmol/L in response to ingested fructose. Glucose appearing in the peripheral circulation as a result of ingestion of 50 g fructose was calculated to be 9.8 +/- 2.4 g. Following the ingestion of fructose, there was a small increase in glucagon but a 2-fold increase in insulin concentration. There was a large transient increase in lactate and alanine concentrations. The total amino acid concentration remained unchanged, as did the urea production rate. In summary, in men fasted overnight, ingestion of 50 g fructose resulted in a modest increase in the circulating glucose concentration. However, it is likely that a larger proportion of the ingested fructose was converted to glucose in the liver and stored as glycogen and that fructose substituted, at least in part, for lactate and alanine as a gluconeogenic substrate. The increase in glucose production occurred even in the presence of an increase in the insulin concentration and an unchanged glucagon concentration. The metabolic fate of the remaining fructose is yet to be determined.

Administration, Oral↗

PubMed2000

Effect of intensive glycemic control on microalbuminuria in type 2 diabetes. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes Feasibility Trial Investigators.

OBJECTIVE: Microalbuminuria can reflect the progress of microvascular complications and may be predictive of macrovascular disease in type 2 diabetes. The effect of intensive glycemic control on microalbuminuria in patients in the U.S. who have had type 2 diabetes for several years has not previously been evaluated. RESEARCH DESIGN AND METHODS: We randomly assigned 153 male patients to either intensive treatment (INT) (goal HbA(1c) 7.1%) or to standard treatment (ST) (goal HbA(1c) 9.1%; P = 0.001), and data were obtained during a 2-year period. Mean duration of known diabetes was 8 years, mean age of the patients was 60 years, and patients were well matched at baseline. We obtained 3-h urine samples for each patient at baseline and annually and defined microalbuminuria as an albumin:creatinine ratio of 0.03-0.30. All patients were treated with insulin and received instructions regarding diet and exercise. Hypertension and dyslipidemia were treated with similar goals in each group. RESULTS: A total of 38% of patients had microalbuminuria at entry and were evenly assigned to both treatment groups. INT retarded the progression of microalbuminuria during the 2-year period: the changes in albumin:creatinine ratio from baseline to 2 years of INT versus ST were 0.045 vs. 0.141, respectively (P = 0.046). Retardation of progressive urinary albumin excretion was most pronounced in those patients who entered the study with microalbuminuria and were randomized to INT. Patients entering with microalbuminuria had a deterioration in creatinine clearance at 2 years regardless of the intensity of glycemic control. In the group entering without microalbuminuria, the subgroup receiving ST had a lower percentage of patients with a macrovascular event (17%) than the subgroup receiving INT (36%) (P = 0.03). Use of ACE inhibitors or calcium-channel blockers was similarly distributed among the groups. CONCLUSIONS: Intensive glycemic control retards microalbuminuria in patients who have had type 2 diabetes for several years but may not lessen the progressive deterioration of glomerular function. Increases in macrovascular event rates in the subgroup entering without albuminuria who received INT remain unexplained but could reflect early worsening, as observed with microvascular disease in the Diabetes Control and Complications Trial.

Adult↗

PubMed2000

Two years of intensive glycemic control and left ventricular function in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM) was a multicenter randomized prospective study of 153 male type 2 diabetic patients to assess the ability to sustain clinically significant glycemic separation between intensive and standard treatment arms. A trend toward an excess of combined cardiovascular events in the intensive treatment arm of this trial was reported earlier. The present analysis was done to evaluate the effect of 2 years of intensive glycemic control on the left ventricular (LV) function. RESEARCH DESIGN AND METHODS: The patients were randomized to intensive step treatment with insulin alone or with sulfonylurea (intensive treatment arm [INT], n = 75) or to standard once-daily insulin injection (standard treatment arm [STD], n = 78) treatment. A total of 136 patients (standard treatment arm [STD], n = 70; INT, n = 66) had radionuclide ventriculography at entry and at 24 months for the assessment of LV function. RESULTS: There was no difference in the mean LV ejection fraction (at entry: STD 57.1+/-9.51%; INT 58.1+/-8.7%; at 24 months: STD 57.3+/-10.8%, INT 59.5+/-10.7%), peak filling rate (at entry: STD 2.6+/-0.7 end diastolic volume per second, INT 2.4+/-0.8 end diastolic volume per second; at 24 months: STD 2.7+/-1.0 end diastolic volume per second, INT 2.5+/-0.7 end diastolic volume per second), or time to peak filling rate (at entry: STD 195.3+/-69.5 ms, INT 185.6 +/-62.4 ms; at 24 months: STD 182.6+/-64.8 ms, INT 179.2+/-61.2 ms) between the 2 treatment arms. A subgroup analysis of 104 patients (STD, n = 53; INT, n = 51) that omitted individuals with intervening cardiac events/revascularization or a change in cardioactive medications also showed no difference in the LV function at entry and at 24 months between the 2 groups. Abnormal LV ejection fraction at baseline predicted cardiac events (interval between cardiac beats [RR] = 2.5). CONCLUSIONS: Two years of intensive glycemic control does not affect the LV systolic or diastolic function in patients with type 2 diabetes.

Blood Glucose↗

PubMed1999

Confirmation of linkage of hereditary partial lipodystrophy to chromosome 1q21-22.

Familial lipodystrophy is a genetically heterogeneous set of disorders characterized by a total or partial absence of subcutaneous fat, diabetes mellitus or impaired glucose tolerance, hyperlipidemia, and hypermetabolism [Senior and Gellis, 1964]. One subtype, familial partial lipodystrophy Dunnigan (FPLD), is a rare autosomal dominant trait that results in an gradual loss of subcutaneous fat in the lower trunk and limbs, Type V hyperlipoproteinemia, hypertriglyceridemia, and insulin-resistant diabetes. Previous reports of this condition have been limited to case reports or very small families. Recently, Peters et al. reported on linkage of five families of Western European descent to a 5.3 cM region on chromosome 1q21-22 between the flanking markers D1S305 and D1S1600 [Peters et al., 1998: Nat Genet 18:292-295]. We performed linkage and haplotype analysis using highly polymorphic, microsatellite markers on a large, multigeneration Caucasian kindred of German ancestry. The maximum two-point lod score achieved was 4.96 at theta(max) = 0 for marker D1S2721. Multipoint analysis gave an overall maximum lod score of 6.27 near marker D1S2721. The results of the haplotype analysis support the minimal candidate region as reported by Peters et al.

Adult↗

PubMed1999

Effect of age on the percentage of hemoglobin A1c and the percentage of total glycohemoglobin in non-diabetic persons.

The purpose of this study was to determine the correlation between age and the percentage of total glycohemoglobin (%tGHb) and that of hemoglobin Alc (%HbA1c) in an adult population without known diabetes. The %tGHb was determined by a semi-automated gravity elution method and by an automated high-performance liquid chromatography (HPLC) method in 210 and 147 subjects without known diabetes, respectively. The %HbA1c, was determined by ion-exchange HPLC in 109 subjects without known diabetes. There was a modest age-related increase in %tGHb and %HbA1c. The mean increase was approximately 0.11% to 0.15% per decade depending on the analytic method used. However, the variance was very large. In conclusion, there is an age-related increase in %tGHb and %HbA1c. However, the increase is only modest and has only a minor effect on a determined reference range in adults.

Adult↗

PubMed1999

Autoimmune hypoglycemia.

Autoimmune hypoglycemia is a rare but fascinating syndrome of hypoglycemia caused by the interaction of endogenous antibodies with insulin or the insulin receptor. Awareness of autoimmune hypoglycemia is important because the syndrome may produce severe neuroglycopenic symptoms and may be confused with the presence of an insulinoma. A correct diagnosis is important to avoid unnecessary surgical intervention in patients who are best treated with conservative support, watchful waiting, or in some cases, immunosuppressive therapy.

Antibodies↗

PubMed1999

Thyroid function and energy intake during weight gain following treatment of hyperthyroidism.

OBJECTIVE: Individuals with hyperthyroidism lose weight despite increased appetite and food intake, and weight is regained after treatment of hyperthyroidism. We asked whether this weight regain is purely a function of lowered metabolic rate coincident with lowered thyroid hormone concentrations or if the weight gain is related to food-energy overconsumption. METHODS: Ten unselected patients with hyperthyroidism treated with 131I were studied. The following measurements were made at 0, 1, 2, 3, 6, and 12 months: total food energy, carbohydrate, fat and protein consumption; serum thyroxine (T4); serum triiodothyronine (T3); T3 resin uptake; serum thyroid stimulating hormone (TSH); weight; height; and 24-hour urinary urea excretion. RESULTS: Inverse changes in body weight and food energy consumption/kg throughout the period of observation was a striking finding (mean initial weight 67.1+/-5 kg, final weight 76.4 kg+/-3 kg, premorbid weight 77.1+/-5 kg). The initial and final food energy intake was 3005+/-199 and 2597+/-137 Kcal/24 hrs, respectively. The thyroid hormone concentrations declined inversely relative to weight gain during the first months of the study, but later the thyroid hormones increased while weight gain continued. Initial serum T4 15.0+/-1 value at three months was 4.0+/-1.0 mg/dl, final T4 11.0+/-1. CONCLUSION: We conclude that weight gain following treatment of hyperthyroidism is due to 1) reduction in metabolic rate consequent upon the decreased thyroid hormone concentrations and 2) food energy intake which was initially greater than required to maintain individuals' premorbid weight. As body weight increased, food intake declined and both reached an asymptotic limit.

Adult↗

PubMed1998

Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0.

Glycogen storage disease type 0 (GSD-0) is a rare form of fasting hypoglycemia presenting in infancy or early childhood and accompanied by high blood ketones and low alanine and lactate concentrations. Although feeding relieves symptoms, it often results in postprandial hyperglycemia and hyperlactatemia. The glycogen synthase (GS) activity has been low or immeasurable in liver biopsies, whereas the liver glycogen content has been only moderately decreased. To investigate whether mutations in the liver GS gene (GYS2) on chromosome 12p12.2 were involved in GSD-0, we determined the exon-intron structure of the GYS2 gene and examined nine affected children from five families for linkage of GSD-0 to the GYS2 gene. Mutation screening of the 16 GYS2 exons was done by single-strand conformational polymorphism (SSCP) and direct sequencing. Liver GS deficiency was diagnosed from liver biopsies (GS activity and glycogen content). GS activity in the liver of the affected children was extremely low or nil, resulting in subnormal glycogen content. After suggestive linkage to the GYS2 gene had been established (LOD score = 2.9; P < 0.01), mutation screening revealed several different mutations in these families, including a premature stop codon in exon 5 (Arg246X), a 5'-donor splice site mutation in intron 6 (G+1T--> CT), and missense mutations Asn39Ser, Ala339Pro, His446Asp, Pro479Gln, Ser483Pro, and Met491Arg. Seven of the affected children carried mutations on both alleles. The mutations could not be found in 200 healthy persons. Expression of the mutated enzymes in COS7 cells indicated severely impaired GS activity. In conclusion, the results demonstrate that GSD-0 is caused by different mutations in the GYS2 gene.

Animals↗

PubMed1998

State-space models of insulin and glucose responses to diets of varying nutrient content in men and women.

Discrete-time state-space models were developed to describe contemporaneous responses of plasma insulin and glucose of normal human subjects. Male and female subjects ingested three consecutive identical meals from isocaloric diets classified as high-carbohydrate, high-fat, high-protein, or standard. Distinctly different glucose and insulin responses were measured in men and women. A seven-state system of linear equations, three in insulin and four in glucose, was identified and estimated to describe responses in men. A six-state system, three in insulin and three in glucose, describes responses in women. Model simulations at 15-min intervals closely match measured concentrations over a 12-h period. Effects of diet content and meal timing on insulin and glucose concentrations were quantified. Dynamic insulin and glucose responses to isocaloric meals of pure carbohydrate, fat, and protein diets were projected on the basis of models developed from mixed diets. The symmetry of the projections indicates that positive excursions in glucose concentrations associated with carbohydrate intake may be matched with negative excursions associated with fat and protein intake to help manage postmeal glucose excursions.

Adult↗

PubMed1998

Stimulation of insulin secretion by fructose ingested with protein in people with untreated type 2 diabetes.

OBJECTIVE: Ingested protein provides substrate for gluconeogenesis and strongly stimulates insulin and glucagon secretion, but it has little effect on the glucose concentration in people with type 2 diabetes. Ingested fructose also is a substrate for gluconeogenesis, modestly stimulates insulin and glucagon secretion, and has little effect on the plasma glucose. Therefore we were interested in determining if ingestion of fructose along with protein would result in an additive, greater than additive, or less than additive effect on circulating insulin, glucagon, and glucose concentrations. RESEARCH DESIGN AND METHODS: Seven male subjects with untreated type 2 diabetes were fasted overnight and then were given either 25 g fructose, 25 g protein, 25 g fructose plus 25 g protein, or water only at 0800. Subjects also ingested 50 g glucose on two separate occasions. Plasma glucose, insulin, C-peptide, glucagon, alpha-amino nitrogen, urea nitrogen, nonesterified fatty acids, and triglyceride concentrations were determined over the subsequent 5 h. RESULTS: The glucose concentration was only modestly increased and the area responses were similar when protein, fructose, or the combination was ingested. Thus, the glucose response to the combination was less than additive. The insulin area response to protein was 2.5-fold greater than to fructose, and the response to the two nutrients was additive and quantitatively similar to the response to 50 g glucose. The glucagon area response was less than additive, i.e., there was an interaction between the protein and fructose that resulted in a smaller than expected response. CONCLUSIONS: When protein and fructose were ingested together, the insulin response was similar to that following ingestion of 50 g glucose. It also was as expected based on the response to the individual nutrients. In contrast, the glucose and glucagon responses were significantly less than expected. These data may be useful in dietary planning for subjects with type 2 diabetes.

Administration, Oral↗

PubMed1998

Acute metabolic response to high-carbohydrate, high-starch meals compared with moderate-carbohydrate, low-starch meals in subjects with type 2 diabetes.

OBJECTIVE: The monosaccharides resulting from the digestion of ingested carbohydrates are glucose, fructose, and galactose. Of these three monosaccharides, only ingested glucose resulted in a large increase in the plasma glucose concentration. Fructose (Metabolism 41:510-517, 1992) and galactose (Metabolism 42:1560-1567, 1993) had only a minor effect. Therefore, we were interested in determining whether we could design a mixed meal, using foods of known monosaccharide, disaccharide, and starch composition, the ingestion of which would result in only a small rise in plasma glucose concentration. RESEARCH DESIGN AND METHODS: The experimental meal was composed of very little readily digestible starch but rather large amounts of fruits and vegetables. It contained 43% carbohydrate, 22% protein, and 34% fat. The results were compared with a second type of meal that contained 55% carbohydrate, 15% protein, and 30% fat, with an emphasis on complex carbohydrates (starch). It also was compared with a third meal that contained 40% carbohydrate, 20% protein, and 40% fat, typical of that consumed by the average American. The test meals were ingested in random order by people with type 2 diabetes who were not treated with oral hypoglycemic agents or insulin. Each subject ingested each type of meal. The same identical meal was ingested at 0800, 1200, and 1700. RESULTS: The integrated 24-h plasma glucose area response was statistically significantly smaller (P < 0.05) after ingestion of the low-starch meals compared with the high-starch, high-carbohydrate meals or the typical American meals. The 24-h integrated serum insulin area response also was statistically significantly less (P < 0.05) after ingestion of the low-starch meals compared with the high-starch meals or the typical American meals. The serum triglyceride area response was similar after ingestion of all three test diets. CONCLUSIONS: A diet in which fruits, nonstarch vegetables, and dairy products are emphasized may be useful for people with type 2 diabetes.

Aged↗

PubMed1998

Ethnic differences in the glycemic response to exogenous insulin treatment in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus was conducted in NIDDM patients to determine if a significant difference in HbA1c could be achieved between groups receiving standard and intensive treatment. We observed differences in the response to exogenous insulin between African-Americans and other intensively treated patients. Therefore, we assessed the variations of response and correlated factors that might explain such differences. RESEARCH DESIGN AND METHODS: One hundred fifty-three men aged 40-69 years with NIDDM for < or = 15 years were randomized to either the standard therapy (n = 78) or the intensive therapy (n = 75) arm. Of the 75 patients in the intensive therapy group, 57 completed the study on insulin therapy alone. Of these, 18 were African-Americans and 39 were non-African-Americans. We conducted an analysis of the data collected to determine differences in baseline characteristics, glycemic response, insulin requirement, body weight, exercise, and basal C-peptide level, factors that may explain a difference in response to insulin therapy. RESULTS: Glycemic control improved in all patients with intensive insulin therapy. African-Americans achieved a greater improvement in HbA1c compared with non-African-Americans with a similar increment in insulin. This difference could not be explained by differences in body weight, activity, concomitant use of other medicines, or insulin-secretory capacity of the pancreas. CONCLUSIONS: We conclude that ethnic differences may exist in the response to insulin therapy. A knowledge of such differences may aid in achieving good glycemic control, especially since minorities have a greater prevalence of and burden from the microvascular complications of diabetes.

Adult↗

PubMed1998

Response to intensive therapy steps and to glipizide dose in combination with insulin in type 2 diabetes. VA feasibility study on glycemic control and complications (VA CSDM).

OBJECTIVE: The feasibility study for the VA Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (VA CSDM) prospectively studied 153 insulin-requiring type 2 diabetes patients, randomized between an intensively treated arm and a standard treatment arm during a mean follow-up of 27 months. The glycemic response to each of the progressive, sequential phases of insulin treatment was assessed, along with the incidence of hypoglycemic reactions and the relative efficacy of different doses of glipizide in combination with fixed doses of insulin. RESEARCH DESIGN AND METHODS: Five medical centers participated; half of the patients were assigned to the intensive treatment arm aiming for normal HbA1c levels. Age of patients was 60 +/- 6 years, duration of diabetes 8 +/- 3 years, and BMI 30.7 +/- 4 kg/m2. A four-step management technique was used, with patients moving to the next step if the operational goals were not met: Phase I, evening intermediate or long-acting insulin; phase II, added day-time glipizide; phase III, two injections of insulin alone; and phase IV, multiple daily insulin injections. Home glucose monitoring measurements were done twice daily and at 3:00 A.M. once a week. Hypoglycemic reactions and home glucose monitoring results were recorded and counted in each of the treatment phases. RESULTS: Baseline HbA1c was 9.3 +/- 1.8%, and fasting plus serum glucose was 11.4 +/- 3.3 mmol/1. Fasting serum glucose fell to near normal in phase I, and remained so in the other treatment phases. An HbA1c separation of 2.1% between the arms was maintained during the course of the study, while the intensive arm kept HbA1c levels below 7.3% (P = 0.001). Most of the decrease in HbA1c occurred with one injection of insulin alone (phase I, -1.4%) or adding day-time glipizide (phase II, -1.9% compared with baseline). HbA1c did not decrease further after substituting two injections of insulin alone, with twice the insulin dose. Multiple daily injections resulted in an additional HbA1c fall (-2.4% compared with baseline). However, two-thirds of the patients were still on one or two injections a day at the end of the study. Changes in home glucose monitoring levels paralleled those of the HbA1c, as did the increments in number of reported hypoglycemic reactions, virtually all either "mild" or "moderate" in character. For the combination of glipizide and insulin (phase II), the only significant effect was obtained with daily doses up to 10 mg a day; there were no significant additional benefits with up to fourfold higher daily doses, and HbA1c levels had an upward trend with doses > 20 mg/day. CONCLUSIONS: A simple regime of a single injection of insulin, alone or with glipizide, seemed sufficient to obtain clinically acceptable levels of HbA1c for most obese, insulin-requiring type 2 diabetes patients. Further decrease of HbA1c demanded multiple daily injections at the expense of doubling the insulin dose and the rate of hypoglycemic events. In combination therapy, doses of glipizide > 20 mg/day offered no additional benefit.

Adult↗