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Biomedical subjects

M Stumvoll

Publications and source records attributed to M Stumvoll.

At least 19 recordsLinked to original sources
PubMed2001

[Polymorphism of pro12Ala in peroxisome proliferator activated receptor gamma 2 (PPAgamma2): beta cell function and insulin sensitivity].

BACKGROUND AND OBJECTIVE: The peroxisome proliferator-activated receptor isoform gamma (PPAR gamma) is a key regulator in lipid and glucose homoeostasis. A common polymorphism (Pro12Ala in PPAR gamma 2, prevalence ca. 25%) was shown to be associated with a decreased risk of type 2 diabetes. Generally, both beta-cell dysfunction and insulin resistance contribute to the development of type 2 diabetes. Therefore, the aim of the present study was to assess the mechanism by which the Ala allele of this polymorphism contributes to the reduced risk for type 2 diabetes. PATIENTS AND METHODS: We studied 51 subjects without (Pro/Pro) and 26 subjects with this polymorphisms (X/Ala) (both groups non-diabetic) by a modified hyperglycaemic clamp which permitted determination of both insulin secretion (in response to glucose, GLP-1 and arginine) and insulin sensitivity. RESULTS: None of the various phases of insulin secretion was significantly different between the 2 genotype groups (all p values > 0.13). In contrast, insulin sensitivity was significantly greater in X/Ala (0.19 +/- 0.03 U) compared to Pro/Pro (0.14 +/- 0.01 U, p = 0.04). In a two-dimensional assessment of insulin sensitivity and secretion, the homozygous alanine carriers appeared to have the most favourable constellation. CONCLUSION: These simultaneously obtained data for insulin secretion and sensitivity strongly suggest that the mechanism by which the Ala allele contributes to a risk reduction for type 2 diabetes most likely involves an increase in insulin sensitivity.

Adult↗
PubMed2001

Avoidance of hypoglycemia restores hypoglycemia awareness by increasing beta-adrenergic sensitivity in type 1 diabetes.

BACKGROUND: Lack of awareness of hypoglycemia is a major limiting factor in the management of type 1 diabetes. OBJECTIVE: To examine whether reduction in the number of episodes of hypoglycemia restores hypoglycemia awareness by influencing beta-adrenergic sensitivity in patients with type 1 diabetes. DESIGN: Controlled interventional study. SETTING: Research unit and outpatient diabetes clinic of a university hospital. PATIENTS: 10 men with type 1 diabetes and hypoglycemia unawareness (mean age [+/-SD], 46 +/- 16 years; mean duration of diabetes, 20 +/- 10 years). INTERVENTION: Strict avoidance of hypoglycemia. MEASUREMENTS: beta-Adrenergic sensitivity was measured by isoproterenol testing before and at 2 and 4 months after strict avoidance of hypoglycemia. Hypoglycemia awareness and catecholamine response were measured by performing hypoglycemic clamp (glucose level, 3 mmol/L [54 mg/dL]) before and after 4 months of avoidance of hypoglycemia. RESULTS: After 4 months, the mean (+/-SE) number of episodes of hypoglycemia (glucose level < 3.9 mmol/L [70 mg/dL]) decreased from 8.4 +/- 0.9 to 1.4 +/- 0.3 per week (P < 0.001). Hemoglobin A(1c) values increased from 0.068 +/- 0.003 (6.8% +/- 0.3%) to 0.077 +/- 0.003 (7.7% +/- 0.3%) (P < 0.001). Autonomic symptom scores during hypoglycemic clamp increased from 1.8 +/- 0.6 to 3.3 +/- 0.7 (P = 0.004) and did not significantly differ from those of normal participants (4.7 +/- 0.8) (P > 0.2). Although catecholamine responses to hypoglycemia were unchanged, the dose of isoproterenol necessary to increase heart rate by 25 beats/min (IC(25)) decreased from 1.96 +/- 0.43 microgram before treatment to 1.09 +/- 0.17 microgram after 4 months of treatment (P = 0.01), a value similar to that in normal participants (0.85 +/- 0.20 microgram) (P > 0.2). Improvements in beta-adrenergic sensitivity (change in IC(25)(-1)) were correlated with improvements in autonomic symptoms (r = 0.65; P = 0.04). CONCLUSIONS: Avoidance of hypoglycemia in patients with type 1 diabetes who have hypoglycemia unawareness seems to restore hypoglycemia awareness, primarily by increasing beta-adrenergic sensitivity.

Adult↗
PubMed2001

Effects of troglitazone on cellular differentiation, insulin signaling, and glucose metabolism in cultured human skeletal muscle cells.

To determine the immediate effect of thiazolidinediones on human skeletal muscle, differentiated human myotubes were acutely (1 day) and myoblasts chronically (during the differentiation process) treated with troglitazone (TGZ). Chronic TGZ treatment resulted in loss of the typical multinucleated phenotype. The increase of muscle markers typically observed during differentiation was suppressed, while adipocyte markers increased markedly. Chronic TGZ treatment increased insulin-stimulated phosphatidylinositol (PI) 3-kinase activity and membranous protein kinase B/Akt (PKB/Akt) Ser-473 phosphorylation more than 4-fold. Phosphorylation of p42/44 mitogen-activated protein kinase (42/44 MAPK/ERK) was unaltered. Basal glucose uptake as well as both basal and insulin-stimulated glycogen synthesis increased approximately 1.6- and approximately 2.5-fold after chronic TGZ treatment, respectively. A 2-fold stimulation of PI 3-kinase but no other significant TGZ effect was found after acute TGZ treatment. In conclusion, chronic TGZ treatment inhibited myogenic differentiation of that human muscle while inducing adipocyte-specific gene expression. The effects of chronic TGZ treatment on basal glucose transport may in part be secondary to this transdifferentiation. The enhancing effect on PI 3-kinase and PKB/Akt involved in both differentiation and glycogen synthesis appears to be pivotal in the cellular action of TGZ.

Adipocytes↗
PubMed2001

Acute stimulation of leptin concentrations in humans during hyperglycemic hyperinsulinemia. Influence of free fatty acids and fasting.

OBJECTIVE: To assess the acute regulation of leptin concentrations by insulin, glucose and free fatty acids (FFAs). DESIGN: Four protocols: saline control experiment (CON); hyperglycemic clamps (approximately 8.3 mmol/l, 120 min) after an overnight fast (12 FAST); after a 36 h fast (36 FAST); and after a 36 h fast during which Intralipid/heparin was given over the last 24 h (36 FAST+FFA). SUBJECTS: Lean, young, healthy volunteers; control group (n=6), experimental group (n=6). MEASUREMENTS: Serum leptin concentrations. RESULTS: Glucose and insulin concentrations were similar during the three clamp protocols. Average FFAs during the last 60 min of the clamp were 671+/-68 microM (CON),109+/-15 microM (12 FAST), 484+/-97 microM (36 FAST) and 1762+/-213 microM (36 FAST+FFA). Leptin concentrations decreased similarly during 36 FAST and 36 FAST+FFA. Leptin concentrations at 120 min (expressed as percentage of mean basal value) were 0.82+/-0.02 (CON), 0.93+/-0.08 (12 FAST) (P=0.29), 1.19+/-0.06 (36 FAST) (P<0.01) and 1.44+/-0.12 (36 FAST+FFA) (P<0.01). CONCLUSION: During a one-day fast leptin concentrations decrease regardless of maintainance of an isocaloric balance. During acute hyperinsulinemic hyperglycemia leptin concentrations increase only after a preceding fast. This increase was most pronounced during simultaneous elevation of FFAs. Overall, our findings are compatible with the hypothesis that leptin secretion may be coupled to triglyceride synthesis rather than to the absolute lipid content of the adipocyte. International Journal of Obesity (2001) 25, 138-142

Adult↗
PubMed2001

A novel use of the hyperinsulinemic-euglycemic clamp technique to estimate insulin sensitivity of systemic lipolysis.

The aim of the present study was to assess whether a standard hyperinsulinemic-euglycemic clamp can provide an estimate for the antilipolytic insulin sensitivity. For this purpose, we infused 9 non-obese, healthy volunteers with [2H5]glycerol and used the glycerol rate of appearance (Ra) in plasma as an index for systemic lipolysis during a standard (1 mU/kg x min, 120 min) and a 3-step (0.1, 0.25, 1.0 mU/kg x min) hyperinsulinemic-euglycemic clamp. The insulin concentration, which half-maximally suppressed lipolysis (EC50) in the three-step clamp, was considered to be the gold standard for the antilipolytic insulin sensitivity. Glycerol Ra decreased from 1.53+/-0.11 micromol/kg x min to 0.60+/-0.09 micromol/kg x min (p <0.001) during the standard clamp. The decrease in Ra at most time points during the standard clamp significantly correlated with the EC50. The highest correlation for the % decrease of glycerol Ra from baseline was found at 60 min (r = 0.96, p < 0.001) making this parameter a useful index for the antilipoytic insulin sensitivity. Neither plasma glycerol nor plasma free fatty acid (FFA) concentrations were significantly correlated with the EC50. In conclusion, the standard hyperinsulinemic-euglycemic clamp in combination with isotopic determination of glycerol Ra provides a reasonable estimate for the antilipolytic insulin sensitivity. In healthy subjects, the parameter best suited to estimate the insulin EC50 (by linear correlation) was the percentage decrease of glycerol Ra at 60 min.

Adult↗
PubMed2001

Effect of the pattern of elevated free fatty acids on insulin sensitivity and insulin secretion in healthy humans.

In order to investigate whether the pattern of elevated free fatty acids (FFAs) has any effect on insulin sensitivity and insulin secretion in humans, we produced 2 distinct serum FFA patterns (PT 1 and 2) by infusing 6 healthy volunteers with 2 different lipid emulsions plus heparin for 24 hours. A hyperglycemic clamp (approx. 8 mM, 140 min) was performed before and 5 and 24 hours after both lipid infusions to determine insulin sensitivity and insulin secretion simultaneously. Total FFAs had increased comparably by 24 hours (2020+/-268 microM in PT 1) and (1812+/-154 microM in PT 2, p =0.24). Serum PT 1 contained 66% saturated FFAs plus monoenes and 34% polyenes, while PT 2 contained 80% saturated FFAs plus monoenes and 20% polyenes. Thus, the ratio of polyunsaturated to saturated plus monoenes was about 0.5 in PT 1 vs. 0.25 in PT 2. In PT 1, the insulin sensitivity index (ISI) decreased by 20 +/- 7% and 27 +/- 10% from basal after 5 and 24 hours, respectively. In PT 2, the ISI decreased significantly more after 5 (41+/-7%, p = 0.008) and 24 hours (52+/-6%, p = 0.005). In contrast, different phases of insulin secretion did not change during the lipid infusion and did not vary between the two FFA profiles. In conclusion, these findings provide preliminary evidence that the composition of elevated serum FFAs influenced insulin sensitivity in humans. The FFA pattern low in polyunsaturated FFAs reduced insulin sensitivity more than the pattern high in polyunsaturated FFAs. In contrast, no effect on insulin secretion was observed.

Adult↗
PubMed2001

Determining significant fold differences in gene expression analysis.

A typical use for RNA expression microarrays is comparing the measurement of gene expression of two groups. There has not been a study reproducing an entire experiment and modeling the distribution of reproducibility of fold differences. Our goal was to create a model of significance for fold differences, then maximize the number of ESTs above that threshold. Multiple strategies were tested to filter out those ESTs contributing to noise, thus decreasing the requirements of what was needed for significance. We found that even though RNA expression levels appears consistent in duplicate measurements, when entire experiments are duplicated, the calculated fold differences are not as consistent. Thus, it is critically important to repeat as many data points as possible, to ensure that genes and ESTs labeled as significant are truly so. We were successfully able to use duplicated expression measurements to model the duplicated fold differences, and to calculate the levels of fold difference needed to reach significance. This approach can be applied to many other experiments to ascertain significance without a priori assumptions.

Expressed Sequence Tags↗
PubMed2001

Insulin resistance and insulin sensitizers.

Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance.

Diabetes Mellitus, Type 2↗
PubMed2001

The prevalent Gly1057Asp polymorphism in the insulin receptor substrate-2 gene is not associated with impaired insulin secretion.

Disruption of the insulin receptor substrate-2 was shown to cause type 2 diabetes in mice. This could be largely attributed to abnormal beta-cell development. In humans, a prevalent polymorphism in insulin receptor substrate-2 (Gly1057Asp) was not found be associated with type 2 diabetes in linkage and association studies. We tested the hypothesis that an extreme challenge of the beta cell might reveal subtle abnormalities in carriers of this polymorphism undetected by conventional insulin secretion tests. Therefore, in addition to assessing beta-cell function by oral glucose tolerance testing (n = 318, normal glucose tolerance), we measured the secretory response to maximal stimulation by hyperglycemia (10 mM), glucagon-like peptide-1, and arginine administered in an additive fashion (n = 77, nondiabetic). The allelic frequency of the Asp allele was approximately 37%. Neither the beta-cell function indices from the oral glucose tolerance test nor the secretory response during the hyperglycemic clamp differed measurably between carriers and controls. Moreover, maximal plasma C-peptide concentrations in response to the combined glucose, glucagon-like peptide-1, and arginine stimulus was not different between Gly/Gly (10,745 +/- 1,186 pmol/liter) and X/Asp (10,800 +/- 490 pmol/liter, P = 0.99). In conclusion, our findings strongly suggest that the Gly1057Asp polymorphism in insulin receptor substrate-2 is not associated with beta-cell dysfunction. The normal maximal insulin secretory response makes it unlikely that this common polymorphism results in abnormal beta-cell development.

Adult↗
PubMed2001

Evidence against a rate-limiting role of proinsulin processing for maximal insulin secretion in subjects with impaired glucose tolerance and beta-cell dysfunction.

In subjects with impaired glucose tolerance (IGT) insulin secretion is impaired. Increased proinsulin/insulin (PI/I) ratios suggest that there is also reduced processing of proinsulin to insulin in this condition. The PI/I ratio in the insulin secretory granule is ideally assessed by plasma measurements in response to acute stimulation of insulin secretion. In the present study we tested the hypothesis that maximal stimulation of insulin secretion results in exhaustion of the proinsulin conversion pathway to insulin. We therefore determined the PI/I ratio in 11 normal glucose-tolerant subjects (NGT) and 11 subjects with IGT in response to glucose (squarewave hyperglycemic clamp, 10 mmol/L), glucagon-like peptide-1 (GLP-1; primed-continuous infusion), and arginine given during the continued GLP-1 infusion. In IGT, insulin levels were significantly lower during the first phase (144 +/- 20 vs. 397 +/- 119 pmol/L; P = 0.02), at the end of the GLP infusion (2142 +/- 350 vs. 5430 +/- 1091 pmol/L; P: = 0.002), and in response to arginine (3983 +/- 375 vs. 8663 +/- 1430 pmol/L; P = 0.005). In response to glucose, the minimum PI/I ratio was significantly higher in IGT (3.4 +/- 0.6%) than in NGT (1.4 +/- 0.5%; P = 0.02), suggesting defective proinsulin processing in this condition. In subjects with IGT, the PI/I ratio decreased significantly after GLP-1 priming (1.7 +/- 0.2%; P = 0.02) and after arginine given during GLP-1 (1.4 +/- 0.2%; P = 0.007) and was not significantly different from those values in NGT (1.3 +/- 0.2% and 1.3 +/- 0.2%, respectively; both P = NS). In conclusion, during maximal stimulation of insulin secretion in subjects with IGT, the PI/I ratio in plasma decreased significantly and was not different from that in normal controls. This strongly argues against the hypothesis that defective processing of proinsulin to insulin represents a major component of the beta-cell dysfunction in IGT.

Adult↗
PubMed2001

Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans.

An increased intramyocellular lipid (IMCL) content, as quantified by (1)H-magnetic resonance spectroscopy ((1)H-MRS), is associated with reduced insulin sensitivity. At present, it is unclear which factors determine IMCL formation and how rapidly IMCL accumulation can be induced. We therefore studied the impact of hyperinsulinemia and elevated circulating nonesterified fatty acid (NEFA) levels on IMCL formation and insulin sensitivity. We further evaluated the influence of a high-fat diet on IMCL storage. In the infusion protocol, 12 healthy male subjects underwent a 6-h hyperinsulinemic-euglycemic glucose clamp with concomitant infusion of Intralipid plus heparin. IMCL was quantified by (1)H-MRS in soleus (SOL) and tibialis anterior (TA) muscle at baseline and then every hour. IMCL levels started to increase significantly after 2 h, reaching a maximum of 120.8 +/- 3.4% (SOL) and 164.2 +/- 13.8% (TA) of baseline after 6 h (both P < 0.05). In parallel, the glucose infusion rate (GIR) decreased progressively, reaching a minimum of 60.4 +/- 5.4% of baseline after 6 h. Over time, the GIR was strongly correlated with IMCL in TA (r = -0.98, P < or = 0.003) and SOL muscle (r = -0.97, P < or = 0.005). In the diet protocol, 12 male subjects ingested both a high-fat and low-fat diet for 3 days each. Before and after completion of each diet, IMCL levels and insulin sensitivity were assessed. After the high-fat diet, IMCL levels increased significantly in TA muscle (to 148.0 +/- 16.9% of baseline; P = 0.005), but not in SOL muscle (to 114.4 +/- 8.2% of baseline; NS). Insulin sensitivity decreased to 83.3 +/- 5.6% of baseline (P = 0.033). There were no significant changes in insulin sensitivity or IMCL levels after the low-fat diet. The effects of the high-fat diet showed greater interindividual variation than those of the infusion protocol. The data from the lipid infusion protocol suggest a functional relationship between IMCL levels and insulin sensitivity. Similar effects could be induced by a high-fat diet, thereby underlining the physiological relevance of these observations.

Adult↗
PubMed2001

Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 gene is associated with increased antilipolytic insulin sensitivity.

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)-gamma2 is associated with reduced transcriptional activity in vitro and increased insulin sensitivity in humans in vivo. The mechanism by which this polymorphism influences insulin sensitivity in humans is unclear. PPAR-gamma2 is mainly expressed in adipocytes, and free fatty acids released from adipose tissue are key mediators of peripheral insulin resistance. Therefore, we examined insulin suppression of lipolysis in 51 subjects without (Pro/Pro) and 17 subjects with the polymorphism (X/Ala). Both groups were lean (BMI <27.0 kg/m2) and matched for age, BMI, waist-to-hip ratio, and sex. The isotopically (infusion of d5 glycerol) determined glycerol rate of appearance was used as an index of lipolysis. Insulin sensitivity of lipolysis was expressed as the insulin concentration resulting in half-maximal suppression (EC50). This was directly determined during a three-step hyperinsulinemic-euglycemic clamp (n = 21) or estimated indirectly during a standard hyperinsulinemic-euglycemic clamp (n = 47). The insulin sensitivity index (ISI) of glucose disposal was 0.095+/-0.006 micromol x kg(-1) x min(-1) x pmol(-1) x l(-1) in the control group and 0.129+/-0.008 micromol x kg(-1) x min(-1) x pmol(-1) x l(-1) in the X/Ala group (P = 0.003). The EC50 was 56+/-2 pmol/l in the control group and 44+/-3 pmol/l in the X/Ala group (P = 0.001). The EC50 of lipolysis and ISI was significantly correlated (r = 0.42, P = 0.002). In conclusion, in lean subjects, the Pro12Ala polymorphism is associated with increased insulin sensitivity of glucose disposal and suppression of lipolysis. This result suggests that an altered transcriptional activity of PPAR-gamma2 in X/Ala subjects either causes a more efficient suppression of lipolysis in adipose tissue, which in turn results in improved insulin-stimulated glucose disposal in muscle, or, alternatively, beneficially affects insulin signaling in both tissues independently of one another.

Adult↗
PubMed2001

The Gly972Arg polymorphism in the insulin receptor substrate-1 gene contributes to the variation in insulin secretion in normal glucose-tolerant humans.

The Gly972Arg polymorphism in the insulin receptor substrate (IRS)-1 was found in some studies to have a higher prevalence in type 2 diabetic subjects than in control subjects. Previously, transfection of IRS-1 with this polymorphism into insulin-secreting cells resulted in a marked reduction of glucose-stimulated insulin secretion compared with the wild-type transfected cells. In the present study, we compared insulin secretion in well-matched normal glucose-tolerant subjects with and without this polymorphism. Several validated indexes of beta-cell function from the oral glucose tolerance test were significantly lower in X/Arg (n = 31) compared with Gly/Gly (n = 181) (P between 0.002 and 0.05), whereas insulin sensitivity (measured with a euglycemic clamp) was not different. During a modified hyperglycemic clamp, insulin secretion rates were significantly lower in Gly/Arg (n = 8) compared with Gly/Gly (n = 36) during the first phase (1,711+/-142 vs. 3,014+/-328 pmol/min, P = 0.05) and after maximal stimulation with arginine (5,340+/-639 vs. 9,075+/-722 pmol/min, P = 0.03). In summary, our results suggest that the Gly972Arg polymorphism in IRS-1 is associated with decreased insulin secretion in response to glucose but not with insulin sensitivity. It is possible that this polymorphism causes insulin resistance at the level of the beta-cell and contributes to the polygenic etiology of type 2 diabetes.

Arginine↗
PubMed2001

Effect of experimental elevation of free fatty acids on insulin secretion and insulin sensitivity in healthy carriers of the Pro12Ala polymorphism of the peroxisome proliferator--activated receptor-gamma2 gene.

The transcription of many genes involved in lipid metabolism is regulated by the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The Pro12Ala polymorphism in the PPAR-gamma2 gene has been associated with reduced transcriptional activity in vitro and increased insulin sensitivity in vivo. Although PPAR-gamma has been demonstrated in human beta-cells, it is unknown whether the Pro12Ala polymorphism plays a role in insulin secretion. Moreover, it is also unknown if and how the effect of free fatty acids (FFAs) on insulin secretion and insulin sensitivity is modulated by the presence of this polymorphism. We therefore performed hyperglycemic clamps (8 mmol/l, 140 min, 5 g arginine bolus at min 120) in 10 healthy subjects with the (X/Ala) polymorphism and in 10 subjects without the polymorphism (Pro/Pro) basally and after 5 h infusion of Intralipid plus heparin. FFA concentrations increased from 473 +/- 61 micromol/l to 1,732 +/- 163 micromol/l in the Pro/Pro and from 372 +/- 46 micromol/l to 1,630 +/- 96 micromol/l in the X/Ala group (P = 0.68). Basally, neither insulin sensitivity nor insulin secretion were significantly different between the two groups. During infusion of Intralipid, first-phase insulin secretion remained unchanged in both groups (P = 0.21). In the Pro/Pro group, second-phase insulin secretion remained unchanged (444 +/- 67 vs. 471 +/- 93 pmol/min) and the response to arginine increased from 5,007 +/- 41 to 6,072 +/- 732 pmol/min. In contrast, in the X/Ala group, there was a decrease of both second-phase insulin secretion (533 +/- 58 to 427 +/- 48 pmol/min, P = 0.02 vs. Pro/Pro) and in the response to arginine (from 7,518 +/- 1,306 to 6,458 +/- 1,040 pmol/min, P = 0.014 vs. Pro/Pro). The insulin sensitivity index decreased comparably in Pro/Pro and X/Ala (to 71 +/- 8 vs. 74 +/- 9% of basal, P = 0.8). In conclusion, these results provide evidence that the Pro12Ala polymorphism in the PPAR-gamma2 gene might be involved in a differential regulation of insulin secretion in response to increased FFAs in humans.

Alanine↗
PubMed2001

Functional significance of the UCSNP-43 polymorphism in the CAPN10 gene for proinsulin processing and insulin secretion in nondiabetic Germans.

Recently, an association of the G allele in UCSNP-43 of calpain 10 with type 2 diabetes and decreased glucose disposal was reported. Calpain 10 is also expressed in pancreatic islets. It is not known, however, whether and how this polymorphism contributes to the biological variation of beta-cell function. We studied 73 nondiabetic subjects from the southwest region of Germany (G/G, n = 41; G/A, n = 29; and A/A, n = 3) using a modified hyperglycemic clamp (10 mmol/l glucose, added glucagon-like peptide 1, final arginine bolus). The genotype distribution was not different between subjects with normal glucose tolerance (n = 56) and those with impaired glucose tolerance (n = 17; P = 0.74, chi2 test). First-phase insulin secretion (adjusted for sex and insulin sensitivity from hyperglycemic clamp) was greater in G/G (2,747 +/- 297 pmol/min) than in G/A + A/A (1,612 +/- 156 pmol/min, P = 0.003). Insulin secretion in response to arginine (adjusted for insulin sensitivity) was also greater in G/G (9,648 +/- 1,186 pmol/min) than in G/A + A/A (5,686 +/- 720 pmol/min, P = 0.04). The acute poststimulus proinsulin-to-insulin ratio was lower in G/G (1.6 +/- 0.4% first phase; 1.6 +/- 0.2% arginine) than in G/A + A/A (4.0 +/- 0.5% first phase, P < 0.001; 2.5 +/- 0.4% arginine, P = 0.03). In conclusion, it appears unlikely that any association of the UCSNP-43 polymorphism alone with type 2 diabetes involves impairment of insulin secretion in our population of German Caucasians. This may be entirely different with specific haplotype combinations.

Adult↗
PubMed2001

Renal gluconeogenesis: its importance in human glucose homeostasis.

Studies conducted over the last 60 years in animals and in vitro have provided considerable evidence that the mammalian kidney can make glucose and release it under various conditions. Until quite recently however, it was generally believed that the human kidney was not an important source of glucose except during acidosis and after prolonged fasting. This review will summarize early work in animals and humans, discuss methodological problems in assessing renal glucose release in vivo, and present results of recent human studies that provide evidence that the kidney may play a significant role in carbohydrate metabolism under both physiological and pathological conditions.

Animals↗