Jonathan C. Levy

Correct Homeostasis Model Assessment (HOMA) Evaluation Uses the Computer Program

tight glycemic control, in the treatment of patients with macroalbuminuria from diabetic nephropathy. In the first case, a 58-year-old woman with type 1 diabetes that was diagnosed when she was 17 years old was found to have 1,260 mg/day of protein in the urine. Her history was pertinent for diabetic retinopathy neuropathy, and for recurrent congestive heart failure. Medications included digoxin, furosemide, Cozaar, and aspirin, as well as NPH and regular insulin twice daily. The HbAlcwas 7.7% (4.1-6.1). The treatment regimen was changed to the insulin pump, and therapy with pentoxifylline (400 mg t.i.d.) was begun. Because of gastrointestinal side effects from the pentoxifylline, the dosage was reduced to 400 mg twice per day, which was tolerated. Three months later, the 24-h urine protein was 284 mg/day, and 6 months after that, 237 mg/day. The HbAlc fluctuated between 7.2 and 7.5% during that time. All other medications were continued as before. In the second case, a 74-year-old man with type 1 diabetes that was diagnosed when he was 42 years old had been noted at age 70 years to have 312 mg/day of protein in the urine. Therapy with 10 mg/day lisinopril was begun. After 18 months, a 24-h urine sample revealed 3,643 mg/day of protein. Therapy with pentoxifylline (400 mg t.i.d.) was begun. Also at that time, the insulin regimen was changed from three injections per day to use of the insulin pump. After 6 months, a 24-h urine sample revealed 1,836 mg of protein. When tested 6 months later, the urinary protein was 1,056 mg/day and after an additional 6 months, it was 490 mg/day Lisinopril therapy was continued during this time. HbAlc levels fluctuated between 7.2 and 8.3% (4.1-6.1) during this time, compared with values between 9.0 and 9.3% before introduction of the insulin pump. In the third case, an 84-year old female who had type 2 diabetes with diabetic retinopathy and peripheral neuropathy was found to have 3,967 mg/day of urinary protein. Her history was pertinent for hypertension and congestive heart failure, for which she was treated with captopril (25 mg t.i.d.) and furosemide (40 mg b.i.d.). Her diabetes was managed with Humulin N and Humulin R in the morning, Humulin R at supper, and Humulin N at bedtime. Pentoxifylline was begun for the proteinuria at a dosage of 400 mg t.i.d. After 4 months, the 24-h urinary protein had been reduced to 733 mg/day, and 1 year later, the urinary protein was 787 mg/day. During this time, HbAlc ranged between 5.8 and 6.5% (4.1-6.1). These cases illustrate that pentoxifylline, in conjunction with intensive therapy for diabetes, may be particularly useful in reducing significant proteinuria. All three patients maintained stable serum creatinine levels in the range of 1.0-1.5 mg/dl. Tight glycemic control was maintained in all patients, and in the second case, there was a significant improvement in HbAlc after insulin pump therapy was introduced. Two patients were taking concomitant ACEls, and the third was on an angiotensin-receptor blocker (ARB). ARBs have been shown in .an animal model to attenuate diabetic nephropathy (7). Further studies to elucidate the mechanism of improved macroalbuminuria by pentoxifylline in conjunction with tight glycemic control in the treatment of diabetic nephropathy should be considered. This treatment appears to be beneficial in forestalling the typically relentless downhill course of diabetic nephropathy.

Three-year efficacy of complex insulin regimens in type 2 diabetes.

BACKGROUND Evidence supporting the addition of specific insulin regimens to oral therapy in patients with type 2 diabetes mellitus is limited. METHODS In this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin and sulfonylurea therapy. Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. RESULTS Median glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (6.9%) insulin-based regimens (P=0.28). However, fewer patients had a level of 6.5% or less in the biphasic group (31.9%) than in the prandial group (44.7%, P=0.006) or in the basal group (43.2%, P=0.03), with 67.7%, 73.6%, and 81.6%, respectively, taking a second type of insulin (P=0.002). [corrected] Median rates of hypoglycemia per patient per year were lowest in the basal group (1.7), higher in the biphasic group (3.0), and highest in the prandial group (5.7) (P<0.001 for the overall comparison). The mean weight gain was higher in the prandial group than in either the biphasic group or the basal group. Other adverse event rates were similar in the three groups. CONCLUSIONS Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated hemoglobin control than patients who added a biphasic insulin-based regimen. Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin. (Current Controlled Trials number, ISRCTN51125379.)

A Genomewide Scan for Loci Predisposing to Type 2 Diabetes in a U.K. Population (The Diabetes UK Warren 2 Repository): Analysis of 573 Pedigrees Provides Independent Replication of a Susceptibility Locus on Chromosome 1q

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.

Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes.

Many aspects of physiology and behavior follow a circadian rhythm. Brain and muscle Arnt-like protein-1 (BMAL1) is a key component of the mammalian molecular clock, which controls circadian oscillations. In the rat, the gene encoding Bmal1 is located within hypertension susceptibility loci. We analyzed the SNP distribution pattern in a congenic interval associated with hypertension in the spontaneously hypertensive rat (SHR), and we show that Bmal1 maps close to a region genetically divergent between SHR and its normotensive (Wistar–Kyoto) counterpart. Bmal1 sequencing in rat strains identified 19 polymorphisms, including an SHR promoter variant that significantly affects Gata-4 activation of transcription in transient transfection experiments. A genetic association study designed to test the relevance of these findings in 1,304 individuals from 424 families primarily selected for type 2 diabetes showed that two BMAL1 haplotypes are associated with type 2 diabetes and hypertension. This comparative genetics finding translated from mouse and rat models to human provides evidence of a causative role of Bmal1 variants in pathological components of the metabolic syndrome.

Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM

Summary The gut hormone, glucagon-like peptide-1 (GLP-1) is a potent insulin secretogogue with potential as a therapy for non-insulin-dependent diabetes mellitus (NIDDM). GLP-1 has been shown to reduce glucose concentrations, both basally, and, independently, in response to a single meal. For it to be an effective treatment, it would need to be administered as a long-acting therapy, but this might not be feasible due to the profound delay in gastric emptying induced by GLP-1. In order to assess the feasibility and efficacy of continuous administration of GLP-1 in NIDDM, we determined the effects of continuous intravenous infusion of GLP-1 (7–36) amide, from 22.00–17.00 hours, on glucose and insulin concentrations overnight and in response to three standard meals, in eight subjects with NIDDM. These were compared with responses to 0.9 % NaCl infusion and responses in six non-diabetic control subjects who were not receiving GLP-1. Effects on beta-cell function were assessed in the basal state using homeostasis model assessment (HOMA) and in the postprandial state by dividing incremental insulin responses to breakfast by incremental glucose responses. To assess possible clinical benefit from priming of beta cells by GLP-1 given overnight only, a third study assessed the effect of GLP-1 given from 22.00–07.30 hours on subsequent glucose responses the next day. Continuous GLP-1 infusion markedly reduced overnight glucose concentrations (mean from 24.00–08.00 hours) from median (range) 7.8 (6.1–13.8) to 5.1 (4.0–9.2) mmol/l (p < 0.02), not significantly different from control subjects, 5.6 (5.0–5.8) mmol/l. Daytime glucose concentrations (mean from 08.00–17.00 hours) were reduced from 11.0 (9.3–16.4) to 7.6 (4.9–11.5) mmol/l (p < 0.02), not significantly different from control subjects, 6.7 (6.5–7.0) mmol/l. GLP-1 improved beta-cell function in the basal state from 62 (13–102) to 116 (46–180) %β (p < 0.02) and following breakfast from 57 (19–185) to 113 (31–494) pmol/mmol (p < 0.02). GLP-1 only given overnight did not improve the glucose responses to meals the next day. In conclusion, continuous infusion of GLP-1 markedly reduced diurnal glucose concentrations, suggesting that continuous GLP-1 administration may be a useful therapy in NIDDM. [Diabetologia (1997) 40: 205–211]

Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes

Aims/hypothesis. Adequate comparison of the relative performance of insulin sensitivity tests is not yet available. We compared the discrimination of four insulin sensitivity tests, commonly used in vivo, across a range of glucose tolerance. Methods. Normal (n = 7), impaired glucose tolerant (n = 8) and Type II (non-insulin-dependent) diabetic subjects (n = 9) had in random order two tests from the following: frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT-MinMod); homeostasis model assessment (HOMA) and 2-h continuous infusion of glucose with model assessment (CIGMA) with immunoreactive or specific insulin; short insulin tolerance tests (ITT). The discriminatory power of tests was assessed by the ratio of the within-subject standard deviation to the underlying between-subject standard deviation (discriminant ratio –DR). The degree to which tests measured the same variable was assessed by comparing rank correlation with the maximum expected correlation given the imprecision of the tests. The unbiased lines of equivalence taking into account the precision of tests were constructed. Results. Reciprocal fasting plasma insulin (FPI–1), HOMA %S and 2-h CIGMA %S, had similar DRs with ITT being less informative. The FSIVGTT-MinMod analysis was able to assess 13 out of 24 subjects and had a performance similar to ITT. Using specific rather than immunoreactive insulin for HOMA-CIGMA did not improve the DR. Reciprocal fasting plasma insulin FPI–1, HOMA %S, 2-h CIGMA %S and SI FSIVGTT intercorrelated more than 90 % of the expected rank correlation given the imprecision of the tests, but ITT gave only limited correlation. Conclusion/interpretation. The HOMA-CIGMA test with immunoreactive insulin provides similar information in distinguishing insulin sensitivity between subjects with normal glucose tolerance, those with impaired glucose tolerance and those with Type II diabetes as does FSIVGTT, whereas ITT is less informative. [Diabetologia (1999) 42: 678–687]

Erectile Dysfunction in Diabetes Mellitus

INTRODUCTION Type 2 diabetes is reaching pandemic levels and young-onset type 2 diabetes is becoming increasingly common. Erectile dysfunction (ED) is a common and distressing complication of diabetes. The pathophysiology and management of diabetic ED is significantly different to nondiabetic ED. AIM To provide an update on the epidemiology, risk factors, pathophysiology, and management of diabetic ED. METHOD Literature for this review was obtained from Medline and Embase searches and from relevant text books. MAIN OUTCOME MEASURES A comprehensive review on epidemiology, risk factors, pathophysiolgy, and management of diabetic ED. RESULTS Large differences in the reported prevalence of ED from 35% to 90% among diabetic men could be due to differences in methodology and population characteristics. Advancing age, duration of diabetes, poor glycaemic control, hypertension, hyperlipidemia, sedentary lifestyle, smoking, and presence of other diabetic complications have been shown to be associated with diabetic ED in cross-sectional studies. Diabetic ED is multifactorial in aetiology and is more severe and more resistant to treatment compared with nondiabetic ED. Optimized glycaemic control, management of associated comorbidities and lifestyle modifications are essential in all patients. Psychosexual and relationship counseling would be beneficial for men with such coexisting problems. Hypogonadism, commonly found in diabetes, may need identification and treatment. Maximal doses of phosphodiesterase type 5 (PDE5) inhibitors are often needed. Transurethral prostaglandins, intracavenorsal injections, vacuum devices, and penile implants are the available therapeutic options for nonresponders to PDE5 inhibitors and for whom PDE5 inhibitors are contraindicated. Premature ejaculation and reduced libido are conditions commonly associated with diabetic ED and should be identified and treated. CONCLUSIONS Aetiology of diabetic ED is multifactorial although the relative significance of these factors are not clear. A holistic approach is needed in the management of diabetic ED.

Studies of Association between the Gene for Calpain-10 and Type 2 Diabetes Mellitus in the United Kingdom

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.

Meta-Analysis and a Large Association Study Confirm a Role for Calpain-10 Variation in Type 2 Diabetes Susceptibility

To the Editor: Variation in the calpain-10 gene (CAPN10 [MIM 605286]) was recently linked and associated with type 2 diabetes mellitus (T2DM) susceptibility (Horikawa et al. 2000). The initial linkage of T2DM to chromosome 2 was found in a population of Mexican Americans from Starr County, Texas (Hanis et al. 1996). Specific combinations of three intronic variants, designated “SNP-43,” “SNP-19,” and “SNP-63,” that capture most of the haplotype diversity at CAPN10 were associated with a three-fold increased risk of T2DM in this population and could account for the observed linkage (Horikawa et al. 2000). Subsequent association and linkage studies of these three polymorphisms in other populations have produced conflicting results, with association being observed in some populations (Baier et al. 2000 [Pima Indian]; Cassell et al. 2002 [South Indian]; Garant et al. 2002 [African American]; Malecki et al. 2002 [Polish]; Orho-Melander et al. 2002 [Finnish/Botnia]), but not others (Evans et al. 2001 [British]; Hegele et al. 2001 [Oji-Cree Indians]; Tsai et al. 2001 [Samoan]; Xiang et al. 2001 [Chinese]; Daimon et al. 2002 [Japanese]; Elbein et al. 2002 [whites from Utah]; Fingerlin et al. 2002 [Finnish]; Rasmussen et al. 2002 [Danish and Swedish]; Horikawa et al. 2003 [Japanese]). We previously reported that another variant, SNP-44 (designated “CAPN10-g4841T→C”; minor allele frequency 16%), located in intron 3 and 11 bp from SNP-43, was independently associated with T2DM in whites from the United Kingdom (Evans et al. 2001). Further studies have provided tentative support for a role of SNP-44 in T2DM and related traits: associations with polycystic ovary syndrome (Gonzalez et al. 2002) and with measures of oral glucose tolerance (Wang et al. 2002; Tschritter et al. 2003) have been reported. Functional studies suggest that SNP-44 is located in an enhancer element and might affect CAPN10 expression (Horikawa et al. 2000). Also, in the U.K., German, Japanese, and South Indian populations, SNP-44 is in perfect linkage disequilibrium (r2=1) with a missense mutation Thr504Ala (SNP-110) and two polymorphisms in the 5′-UTR (SNP-134 and SNP-135) (Evans et al. 2001; Cassell et al. 2002; Y. Horikawa and P. E. Schwarz, unpublished data). To assess the association of SNP-44 with T2DM more comprehensively, we performed a meta-analysis of all published SNP-44/T2DM association study data. To identify all relevant published studies, we searched PubMed using the keywords “calpain 10,” “diabetes,” “44,” “SNP 44,” “CAPN10,” and “type 2,” in different combinations. When necessary, authors were contacted to obtain exact genotype numbers, so that precise odds ratios (ORs) from each study could be calculated. Our search identified 10 published case/control studies, consisting of 3,303 subjects. The studies were spread across a number of ethnic groups: British (three studies, Evans et al. 2001); Chinese (Wang et al. 2002); Japanese (Daimon et al. 2002; Horikawa et al. 2003); Finnish/Botnia (two studies, Orho-Melander et al. 2002); South Indian (Cassell et al. 2002); and Mexican American (Horikawa et al. 2000). The frequency of the T2DM-associated SNP-44 C allele (allele 2) ranged from 6% in Mexican Americans to 25% in the Botnia I control population. There was no evidence for OR heterogeneity (Q test P=.27), and, although these studies are only a small sample from the many existing T2DM genetic resources, a funnel-plot analysis (Egger et al. 1997) suggested an absence of publication bias (P=.44). A Mantel-Haenszel meta-analysis of these studies showed that the C allele was associated with increased risk of T2DM (OR 1.17 [1.02–1.34], P=.02). Three transmission/disequilibrium tests (TDT) had been performed (Evans et al. 2001; Cassell et al. 2002; Orho-Melander et al. 2002). The combined TDT results demonstrated that the C allele was significantly overtransmitted (117 transmitted vs. 77 not transmitted, P=.004) from heterozygous parents to diabetic offspring. Although this result cannot be considered independent replication, as proband data was included in the case/control meta-analysis from two of the TDT studies (Evans et al. 2001; Cassell et al. 2002), it provides evidence that the association is not due to population stratification. Of the 10 studies in the meta-analysis, only 1 reported a significant (P<.05) association (Evans et al. 2001). However, these studies were small and the mean power to detect an OR of 1.17 at P<.05 was ∼11% (range 5%–14%). In the context of genetic association studies, which test many polymorphisms in numerous candidate genes, a P value of .02 can only be considered evidence suggestive of a real association. We therefore genotyped SNP-44 in an additional 4,213 subjects: 3,274 white European subjects from four case/control studies (one British, two German, and one Czech); 691 Japanese subjects from two case/control studies; and 248 Mexican (mestizo) subjects from Mexico City and Orizaba City from one case/control study. Overall, this provided 2,056 subjects with T2DM and 2,157 controls, and a power of ∼80% to detect an OR of 1.17. Clinical details of the study subjects are presented in table 1; further details are available as supplementary information from the authors. All studies were approved by the relevant ethics committee, and all subjects gave their informed consent. Table 1 Clinical Characteristics of Subjects in Study[Note] When all the studies were combined, there was no evidence for between-studies OR heterogeneity (Q test P=.23); a Mantel-Haenszel fixed-effects model was therefore used for subsequent analysis. Meta-analysis of the new studies gave an OR for the SNP-44 C allele of 1.18 (1.04–1.34), P=.01 (fig. 1). A combined meta-analysis of all previously published data and our new data gave an OR of 1.17 (1.07–1.29), P=.0007. All study populations were in Hardy-Weinberg equilibrium except the T2DM cohort of Horikawa et al. 2003 (P=.005) and the control population of the third Japanese study (P=.02). Although these deviations may be due to random fluctuation and multiple-hypothesis testing, they contributed a large amount to heterogeneity (27% of the Q statistic); excluding these studies, the SNP-44 C allele OR for the new studies was 1.23 (1.07–1.40), P=.003; the overall OR was 1.19 (1.08–1.31), P=.0005. This OR is of similar magnitude to that of E23K (Gloyn et al. 2003; Love-Gregory et al. 2003; Nielsen et al. 2003) and Pro12Ala (Altshuler et al. 2000), the other common variants confirmed as T2DM-susceptibility polymorphisms. An OR of 1.17 is low and may help explain why there is little evidence for linkage of the CAPN10 region to T2DM in most populations. The haplotypes responsible for the CAPN10 linkage seen in the Mexican American population were associated with a higher T2DM OR (∼3.0) and were more likely to be detected by linkage analysis (Horikawa et al. 2000). These haplotypes are less common in other populations. Figure 1 Mantel-Haenszel OR meta-analysis plot (fixed effects) for SNP-44 association with T2DM. Point estimates and 95% CLs for each previously published, new, and combined case/control study. SNP-44 is in perfect linkage disequilibrium (r2=1) with the missense mutation, Thr504Ala, and two SNPs (SNP-134 and SNP-135) in the 5′-UTR and therefore may not be the causal variant. Further haplotype and functional analyses are required to confirm which of these polymorphisms contribute to T2DM susceptibility. In conclusion, our results have confirmed that a CAPN10 haplotype defined by the SNP-44 polymorphism predisposes to T2DM. Meta-analyses of published genetic associations, combined with large replication studies, are a powerful approach to detecting susceptibility variants in common disease.

Normalization of Insulin Responses to Glucose by Overnight Infusion of Glucagon-Like Peptide 1 (7–36) Amide in Patients With NIDDM

Glucagon-like peptide 1 (GLP-1) is a natural enteric incretin hormone, which is a potent insulin secretogogue in vitro and in vivo in humans. Its effects on overnight glucose concentrations and the specific phases of insulin response to glucose and nonglucose secretogogues in subjects with NIDDM are not known. We compared the effects of overnight intravenous infusion of GLP-1 (7-36) amide with saline infusion, on overnight plasma concentrations of glucose, insulin, and glucagon in eight subjects with NIDDM. The effects on basal (fasting) β-cell function and insulin sensitivity were assessed using homeostasis model assessment (HOMA) and compared with seven age- and weight-matched nondiabetic control subjects. The GLP-1 infusion was continued, and the first- and second-phase insulin responses to a 2-h 13 mmol/l hyperglycemic clamp and the insulin response to a subsequent bolus of the nonglucose secretogogue, arginine, were measured. These were compared with similar measurements recorded after the overnight saline infusion and in the control subjects who were not receiving GLP-1. The effects on stimulated β-cell function of lowering plasma glucose per se were assessed by a separate overnight infusion of soluble insulin, the rate of which was adjusted to mimic the blood glucose profile achieved with GLP-1. Infusion of GLP-1 resulted in significant lowering of overnight plasma glucose concentrations compared with saline, with mean postabsorptive glucose concentrations (2400–0800) of 5.6 ± 0.8 and 7.8 ± 1.4 mmol/l, respectively (P < 0.0002). Basal β-cell function assessed by HOMA was improved from geometric mean (1 SD range), 45% β (24–85) to 91% β (55–151) by GLP-1 (P < 0.0004). First-phase incremental insulin response to glucose was improved by GLP-1 from 8 pmol/l (-–33) to 116 pmol/l (12–438) (P < 0.005), second-phase insulin response to glucose from 136 pmol/l (53–352) to 1,156 pmol/l (357–3,748) (P < 0.0002), and incremental insulin response to arginine from 443 pmol/l (172–1,144) to 811 pmol/l (272–2,417) (P < 0.002). All responses on GLP-1 were not significantly different from nondiabetic control subjects. Reduction of overnight glucose by exogenous insulin did not improve any of the phases of stimulated β-cell function. Prolonged intravenous infusion of GLP-1 thus significantly lowered overnight glucose concentrations in subjects with NIDDM and improved both basal and stimulated β-cell function to nondiabetic levels. It may prove to be a useful agent in the reduction of hyperglycemia in NIDDM.