SEARCH · PubMed Health

Results for “Glycemic variability”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 235 records · Page 13Linked to original sources

PubMed2026

OCT1 Variants Are Associated with Metformin Clearance and Gluconeogenesis: Mechanistic Insights for Youth-Onset Type 2 Diabetes in the MIGHTY Study.

AIMS/HYPOTHESIS: Behavioral and phenotypic characteristics do not fully explain variability in African Americans with youth-onset type 2 diabetes (Y-T2D) treated with metformin with or without liraglutide. We hypothesized that biological heterogeneity, including genetic variation in the metformin transporter OCT1, influences metformin pharmacokinetics and hepatic glucose flux. Therefore, we sought to characterize metformin pharmacokinetics in Y-T2D and evaluate genetic variants known to modulate metformin efficacy in adults to determine the mechanisms underlying variation in treatment response. METHODS: We evaluated genetic variants related to metformin transport and mechanisms of action in 30 Y-T2D using a candidate-gene approach to evaluate the association of pharmacogenetic variants with fasting glucose and gluconeogenesis. In a subset of Y-T2D randomized to 3 months of metformin (n=11) or metformin and liraglutide (n=8), we constructed a metformin population pharmacokinetic model and evaluated gene variant associations. RESULTS: A one-compartment first-order absorption and elimination pharmacokinetic model provided the optimal fit. Metformin pharmacokinetic parameters were similar by group and not related to glycemia. The rs628031_OCT1 A allele was associated with greater metformin clearance. The rs622342_OCT1 C allele was associated with lower post-treatment fractional gluconeogenesis (β [95% CI] = -8.8 [-14.13, -3.47] %, Adjusted R2 = 0.56, P = 0.003). The rs7903146_TCF7L2 T allele was associated with greater reductions in fasting glucose among those treated with metformin + liraglutide (β = -1.32 [-2.42, -0.22] mmol/L, Adjusted R2 = 0.8, P<0.002), but baseline glucose and gluconeogenesis (P<0.0001) were the strongest predictors of post-treatment glycemia. CONCLUSION/INTERPRETATION: In Y-T2D, OCT1 gene variants rs628031 and rs622342 were associated with metformin clearance and gluconeogenesis, respectively. TCF7L2 variant rs7903146 may contribute to differences in glycemic response in youth treated with metformin and liraglutide. These findings suggest genetic variants may be important for understanding variable metformin response in Y-T2D.

SLC22A1↗

PubMed2004

Hypoglycemia in type 2 diabetes: a critical review.

Hypoglycemia is the most important barrier to tight glycemic control. Although severe hypoglycemia is uncommon, milder events can occur so often that they represent a deterrent to intensifying treatment. High-risk patient behaviors are the most important cause for episodes for which a cause can be identified. Because symptoms are an unreliable way of establishing the diagnosis, SMBG should be considered for the patients at highest risk, particularly as they approach their glycemic targets. SMBG is superior to HbA1c in forecasting the hypoglycemia rate because it provides information about glucose variability--an independent risk factor. Patient education and medication changes are potential ways of reducing the hypoglycemia rate. However, it remains to be proven that patient education is beneficial in this regard.

Circadian Rhythm↗

PubMed2005

Serum glucose concentration and ACP1 genotype in healthy adult subjects.

Acid phosphatase locus 1 (ACP 1 ) or cytosolic low molecular weight protein tyrosine phosphatase is a polymorphic enzyme that can hydrolyze phosphotyrosine-containing peptides of the human insulin receptor and of band 3 protein. High-activity ACP 1 may favor an increase in serum glucose concentration through a depression of insulin action and through inactivation of aldolase, phosphofructokinase, and glyceraldehyde-3-phosphate dehydrogenase induced by dephosphorylation of band 3 protein. In diabetic subjects, we have previously reported lower serum glucose concentration in subjects with low-activity ACP 1 A and AB phenotypes. We have now studied the relationship between serum glucose concentration and ACP 1 genotype in a sample of 137 healthy adult workers of our university. In males, serum glucose concentration is significantly higher in medium-high- than in low-activity ACP 1 genotypes. With advancing age in males, there is a progressive increase in glycemic differential between medium-high- and low-activity ACP 1 genotypes. The data suggest that normal variability of ACP 1 genotype influences serum glucose concentration in normal individuals. Such influence depends on sex and in males becomes more marked with advancing age.

Adult↗

PubMed2006

Current practice of insulin pump therapy in children and adolescents - the Hannover recipe.

Increasing evidence points to the importance of achieving low blood glucose variability and also a low hemoglobin A1c (HbA1c) to prevent diabetic late complications. Continuous subcutaneous insulin infusion (CSII) is associated with lower blood glucose variability in children. Frequent indications for starting CSII in youth are recurrent hypoglycemia, need for increased flexibility, poor glycemic control, dawn phenomenon, or needle phobia. At our center, about one-third of all patients across all age groups are currently on CSII. Although the average glycemic control is not very different from those on multiple daily injections, fewer patients are seen in the segment of very high and very low HbA1c with CSII. Across centers, the 'recipes' tailoring CSII treatment to individual patients and cultures are based more on experience than on evidence. However, several typical pediatric features have been identified. Patterns of the hourly basal rate and prandial insulin requirements vary with age. While many adolescents have increased requirements at dawn and dusk, young children show increasing needs in the second half of the day. Low insulin requirements, particularly in neonates, may need insulin dilution. The selection of catheters and needles has to be appropriate for the age. The opportunity to have an electronic memory read-out of all entries and alarms offers new possibilities of therapeutic monitoring, particularly in those youth not keeping good logbooks. This feature can be helpful, if a trustful relationship between the diabetes team and the family is established.

Adolescent↗

PubMed1972

Subhuman primate pregnancy complicated by streptozotocin-induced diabetes mellitus.

Polydipsia, polyuria, polyphagia, and glucosuria followed the administration of streptozotocin to 6 nonpregnant and 15 pregnant monkeys (Macaca mulatta) in the first trimester of pregnancy. The diabetogenic action of the drug was also reflected in an induced but variable deterioration in maternal intravenous glucose tolerance and a marked attenuation of maternal plasma insulin responsiveness to intravenous glycemic stimuli. The products of conception were examined in 29 pregnancies. The neonates and the placentas of the streptozotocin-treated pregnant animals were significantly heavier than average for the period of gestation, polyhydramnios was consistently present, and there was an increase in the incidence of third trimester stillbirths. The fetal and maternal plasma glucose, insulin, and growth hormone concentrations were examined after the intravascular administration of glucose or a solution of mixed amino acids to the fetus in the third trimester. The neonatal plasma responses to similar insulinogenic stimuli were also examined.Fetal and neonatal base line plasma insulin concentrations were significantly elevated compared to those of the controls. The administration of intravascular glucose to the fetus, mother, or neonate was associated with a prompt 2-to 5-fold increase in fetal or neonatal plasma insulin concentrations. These findings contrast to the unresponsiveness of the pancreatic islet tissue we reported in normal subhuman primate pregnancy. The intravascular infusion of a relatively low concentration of mixed amino acids (2 mg/min) to the conceptii from the streptozotocin-treated pregnancies was associated with an elevation in fetal and neonatal plasma insulin levels, whereas normal monkey fetuses and neonates required a 10-fold greater concentration of amino acids in the infusate for similar responses. The induced hyperaminoacidemia or hyperglycemia did not consistently alter plasma growth hormone concentrations in the conceptii from normal or streptozotocin-treated pregnancies. These data provide evidence that maternal glucose intolerance during pregnancy is associated with enhanced fetal and neonatal pancreatic islet cell responsiveness to glucose and mixed amino acids. Although the specific mechanism(s) that alters both the sensitivity and responsiveness of the normal pancreatic fetal islet to insulinogenic stimuli remains unclear, the data do indicate that insulin-dependent maternal hyperglycemia and hyperaminoacidemia, separately or in combination could contribute to the fetal hyperinsulinemia of pregnancies complicated by diabetes mellitus. Moreover, the overall experiences with these streptozotocin-treated animals suggest that a subhuman primate model may be available to examine directly the antenatal pathophysiology of abnormal carbohydrate metabolism.

Amino Acids↗

PubMed1993

Incidence of gross proteinuria in older-onset diabetes. A population-based perspective.

A few population-based studies describe the incidence of gross proteinuria in people with diabetes. We performed a population-based study in southern Wisconsin of diabetic individuals diagnosed at > or = 30 yr of age either taking insulin (n = 398) or not taking insulin (n = 441). The presence of gross proteinuria (> or = 0.3 g/L) was determined by means of a reagent strip. The incidence of proteinuria in the 4-yr interval was 17.3% (95% CI 13.6-21.0) in those taking insulin and 10.7% (95% CI 7.8-13.6) in those not taking insulin. The relative risk of developing proteinuria for those in the highest level of total pack-yr smoked compared with those who had never smoked was 2.0 (95% CI 1.2-3.3) for those taking insulin and 2.5 (95% CI 1.3-4.5) for those not taking insulin. After controlling for other risk variables, the incidence of gross proteinuria was also associated with higher GHb. These data suggest that smoking and glycemic control, both potentially modifiable factors, are significant risk factors for the development of gross proteinuria.

Adult↗

PubMedDate not supplied

Response to insulin treatment and survival in 104 cats with diabetes mellitus (1985-1995).

Medical records of 104 cats with diabetes mellitus were reviewed. Information from 54 cats that had multiple blood glucose concentrations evaluated at least 5 times over a minimum of 3 months, beginning at the time insulin treatment was initiated, was used to evaluate the efficacy of insulin in treating diabetes mellitus. Fourteen of 54 cats were treated with protamine zinc insulin (PZI), 26 with ultralente insulin, and 14 with lente insulin. Six, 29, and 19 cats had good, mediocre, and poor glycemic control, respectively, based on mean blood glucose concentrations, whereas 31, 21, and 2 owners thought clinical response was good, mediocre, and poor, respectively. No significant difference was found in glycemic control among cats treated with PZI, ultralente, or lente insulin. Glycemic control was significantly (P < .05) better in 33 cats without than in 21 cats with concurrent disease. All 104 cats were used to calculate survival data. Fifty-one of 104 cats were alive at the time of the study. Mean (+/- standard deviation [SD]) and median survival times were 24 (+/- 16) and 20 months, respectively, in the 51 cats still alive at the end of the evaluation, and 25 (+/- 4) and 17 months, respectively, in the 53 cats that had died during the period of evaluation. Pancreatic abnormalities identified in 37 cats that underwent necropsy included chronic pancreatitis (n = 17), acute to subacute pancreatitis (n = 2), exocrine pancreatic adenocarcinoma (n = 7) and adenoma (n = 1), islet cell atrophy and vacuolar degeneration (n = 27), and islet amyloidosis (n = 8). No association was found between glycemic control and islet amyloidosis or exocrine pancreatic neoplasia, or between survival time and chronic pancreatitis, islet amyloidosis, or exocrine pancreatic neoplasia. In conclusion, diabetic cats evaluated in this study showed a variable response to exogenously administered insulin, ranging from excellent to poor. By maintaining mean blood glucose concentrations under 300 mg/dL, clinical signs were improved, and owners were satisfied with insulin treatment. Concurrent potentially insulin-antagonistic diseases were common and deleteriously affected glycemic control and survival time.

Animals↗

PubMed2006

Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft.

Islet grafts can induce insulin independence in type 1 diabetic patients, but their function is variable with only 10% insulin independence after 5 years. We investigated whether cultured grafts with defined beta cell number help standardize metabolic outcome. Nonuremic C-peptide-negative patients received an intraportal graft with 0.5-5.0 x 10(6) beta cells per kilogram of body weight (kg BW) under antithymocyte globulin and mycophenolate mofetil plus tacrolimus. Metabolic outcome at posttransplant (PT) month 2 was used to decide on a second graft under maintenance mycophenolate mofetil/tacrolimus. Graft function was defined by C-peptide >0.5 ng/ml and reduced insulin needs, metabolic control by reductions in HbA(1c), glycemia coefficient of variation, and hypoglycemia. At PT month 2, graft function was present in 16 of 17 recipients of >2 x 10(6) beta cells per kg BW versus 0 of 5 with lower number. The nine patients with C-peptide >1 ng/ml and glycemia coefficient of variation of <25% did not receive a second graft; five of them were insulin-independent until PT month 12. The 12 others received a second implant; it achieved insulin-independence at PT month 12 when the first and second graft contained >2 x 10(6) beta cells per kg BW. Of the 20 recipients of at least one graft with >2 x 10(6) beta cells per kg BW, 17 maintained graft function and metabolic control up to PT month 12. At PT month 12, beta cell function in insulin-independent patients ranged around 25% of age-matched control values. Thus, 1-year metabolic control can be reproducibly achieved and standardized by cultured islet cell grafts with defined beta cell number.

Adolescent↗

PubMed1998

Using carbohydrate counting in diabetes clinical practice.

Carbohydrate counting is a meal planning approach used with clients who have diabetes that focuses on carbohydrate as the primary nutrient affecting postprandial glycemic response. The concept of carbohydrate counting has been around since the 1920s, but it received renewed interest after being used as 1 of 4 meal planning approaches in the Diabetes Control and Complications Trial. In the trial, carbohydrate counting was found to be effective in meeting outcome goals and allowed flexibility in food choices. Recent practice pattern surveys have shown an increasing interest in and use of carbohydrate counting for medical nutrition therapy for persons with diabetes. Carbohydrate counting can be used by clients with type 1, type 2, and gestational diabetes. Three levels of carbohydrate counting have been identified based on increasing levels of complexity. Level 1, or basic, introduces clients to the concept of carbohydrate counting and focuses on carbohydrate consistency. Level 2, or intermediate, focuses on the relationships among food, diabetes medications, physical activity, and blood glucose level and introduces the steps needed to manage these variables based on patterns of blood glucose levels. Level 3, or advanced, is designed to teach clients with type 1 diabetes who are using multiple daily injections or insulin infusion pumps how to match short-acting insulin to carbohydrate using carbohydrate-to-insulin ratios. All 3 levels emphasize portion control and offer opportunities for using creative teaching methods, such as "food labs," and use of a variety of carbohydrate resource tools and publications. In this article, glycemic effects of protein, fat, and fiber intake are discussed for persons with type 1 and type 2 diabetes. Decision trees are introduced for each level of carbohydrate counting and show the usual progression through each level. Carbohydrate counting as a meal planning approach offers variability of food choices with the potential for improving glycemic control. Research opportunities are available for those interested in comparing carbohydrate counting with other meal planning approaches for clients with diabetes and the effects on clinical outcomes.

Diabetes Mellitus↗

PubMed2000

[Relations of glycemic control to diabetic nephropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM)--a pair-matched case-control study].

OBJECTIVE: To describe the relations between glycemic control and development of diabetic nephropathy (DN) in patients with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: A retrospective analysis was carried out on two groups of NIDDM patients, one group without proteinuria (< 300 mg/day, n = 106) and the other group with proteinuria (> or = 500 mg/day, n = 106). The two groups were matched by age <or= +/- 3yrs, sex, race and resident place. Information of these subjects including demographic, history of diseases, family history of diseases, life-style and behavior style was obtained by self-administered questionnaire. Variables including systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), quantity of protein in 24-h urine were measured. Successful glycemic control denoted that the mean value of FBG's surveillance was less than 140 mg/dl after the occurrence of DM (the duration to the development of DN for the patients with DN.). Conditional logistic regression analysis was carried out. RESULTS: Results from univariate analysis showed that development of proteinuria was associated with glycemic control, the FBG level at diagnosis of NIDDM and the highest FBG level in the past. The corresponding odd ratios (OR) with 95% confidence intervals (CI) were 0.43 (0.25 - 0.75); 1.34 (1.05 - 1.72) and 1.35 (1.07 - 1.70) respectively. When data were adjusted by possible confounding factors, the relation of glycemic control to DN still existed, but the other two relations disappeared. CONCLUSION: Successful glycemic control decreased the occurrence risk of DN, independent of other risk factors including diabetic duration.

Adult↗

PubMedDate not supplied

[Autonomic neuropathy in diabetes mellitus].

AIMS: We analyse the different studies conducted on the prevalence, aetiopathology, clinical symptoms and treatment of diabetic autonomic neuropathy (AN), together with its involvement in the mortality of patients. DEVELOPMENT: AN can affect any part of the nervous system to varying degrees and at different moments in time, and its prevalence is significant in any of the stages of diabetes. The aetiopathogenesis of AN results from a multifactorial process involving metabolic disorders triggered by the activation of the polyolic pathway, microangiopathy and alterations affecting the synthesis of essential fatty acids due to hyperglycemia, which is made worse by a deficient regeneration of nerve tissue. Any of the systems innervated by the autonomous nervous system can be affected; the initial symptoms are insidious and of little cause for concern until the more advanced stages of the disease. The chief dysfunctions affect the cardiovascular, digestive, genitourinary and thermoregulatory systems. How AN courses in time varies from patient to patient and depends on the glycemic control that is carried out. Its presence is a factor that increases the mortality rate in diabetic patients. CONCLUSIONS: The prevalence of AN is notable, and the symptoms of autonomic dysfunction are usually under-diagnosed owing to its variability, lack of specificity and the wide range of symptoms. It is important to recognise this entity because of its effects on increasing morbidity and mortality, although they can be reduced by means of a strict glycemic control and specific treatment.

Autonomic Nervous System↗

PubMed2006

Management strategies for brittle diabetes.

Type 1 diabetes is an intrinsically unstable condition. However, the term "brittle diabetes" is reserved for those cases in which the instability, whatever its cause, results in disruption of life and often recurrent and/or prolonged hospitalization. It affects 3/1000 insulin-dependent diabetic patients, mainly young women. Its prognosis is poor with lower quality of life scores, more microvascular and pregnancy complications and shortened life expectancy. Three forms have been described: recurrent diabetic ketoacidosis, predominant hypoglycemic forms and mixed instability. Main causes of brittleness include malabsorption, certain drugs (alcohol, antipsychotics), defective insulin absorption or degradation, defect of hyperglycemic hormones especially glucocorticoid and glucagon, and above all delayed gastric emptying as a result of autonomic neuropathy. Psychosocial factors are very important and factitious brittleness may lead to a self-perpetuating condition. The assessment of brittle diabetes requires quantification of the variability of blood glucose levels. To quantify instability, measures which have been developed, include Mean Amplitude of the largest Glycemic Excursions (MAGE), Mean Of Daily Differences (MODD), Lability Index (LI), Low Blood Glucose Index (LBGI), Clarke's score, Hyposcore, and continuous blood glucose monitoring. Once psychogenic problems have been excluded, therapeutic strategies require firstly, the treatment of underlying organic causes of the brittleness whenever possible and secondly optimising standard insulin therapy using analogues, multiple injections and consideration of Continuous Subcutaneous Insulin Infusion. Alternative approaches may still be needed for the most severely affected patients. Isolated islet transplantation (IIT), which restores glucose sensing, should be considered in cases of hypoglycaemic unawareness and/or lability especially if the body mass index is < 25, but with current immunosuppressive protocols patients must have normal renal function and preferably no plans for pregnancy. Implantable pumps have advantages for patients who either weigh more than 80 kgs or have abnormalities of kidney or liver function or are highly sensitised.

Diabetes Mellitus, Type 1↗

PubMed2006

The insertion/deletion polymorphism in the angiotensin-converting enzyme gene and hypoglycemia awareness in patients with type 1 diabetes.

Impaired hypoglycemia awareness affects approximately 25% of all patients with type 1 diabetes (T1DM). Duration of diabetes and tight glycemic control represent main risk factors of impaired hypoglycemia awareness. However, even among patients with good glycemic control and longstanding T1DM, awareness of hypoglycemia may be intact. Genetic factors might explain some of this remaining variability. Recently, the insertion/deletion ( I/ D) polymorphism in angiotensin converting enzyme gene ( ACE) was shown to be associated with significantly higher risk of hypoglycemic events in subjects with T1DM. Here, we studied the effects of genetic polymorphisms in the ACE on impaired hypoglycemia awareness in 231 Caucasian T1DM patients. Hypoglycemia awareness status was determined using standardized questionnaires (Clarke et al. and Edinburgh Hypoglycemia Scale). ACE I/ D genotype was determined by PCR amplification of the respective fragments from intron 16 of the ACE and size fractionation (I allele frequency=0.49; P=0.74 for Hardy-Weinberg equilibrium). In the logistic regression analysis, significant risk factors of impaired hypoglycemia awareness were duration of diabetes, C-peptide and HbA (1c) (all P<0.01). However, no significant effect of the I/ D polymorphism on impaired hypoglycemia awareness was observed with and without adjustment for age, diabetes duration, C-peptide and HbA (1c). Even though the study provides a relatively large dataset, it is possible that small differences may have been missed.

Adult↗

PubMed2001

Recombinant DNA technology in the treatment of diabetes: insulin analogs.

After more than half a century of treating diabetics with animal insulins, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogs were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid-, intermediate-, and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analog, lispro, confirmed the hopes by showing that improved glycemic control can be achieved without an increase in hypoglycemic events. Two new insulin analogs, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States, and several other analogs are being intensively tested. Thus, it appears that a rapid acceleration of basic and clinical research in this arena will be seen, which will have direct significance to both patients and their physicians. The introduction of new short-acting analogs and the development of the first truly long-acting analogs and the development of analogs with increased stability, less variability, and perhaps selective action, will help to develop more individualized treatment strategies targeted to specific patient characteristics and to achieve further improvements in glycemic control. Data on the currently available and tested analogs, as well as data on those currently being developed, are reviewed.

Amino Acid Sequence↗

PubMed1993

Effect of hepatic nerves on disposition of an intraduodenal glucose load.

We examined the disposition of a continuous 4-h intraduodenal glucose infusion (8 mg.kg-1 x min-1, labeled with [1-13C]glucose and [3-3H]glucose) in nine conscious hepatic-denervated dogs. Cumulative net hepatic uptakes (in grams of glucose equivalents) were 13.7 +/- 2.5 glucose, 3.1 +/- 0.6 gluconeogenic amino acids, and 0.8 +/- 0.1 glycerol. Net hepatic glycogen synthesis totalled 11.0 +/- 0.9 g, 55-62% via the direct pathway. All values were similar to those in hepatic-innervated dogs. Glycogen synthase activity and rate of glycogen synthesis were positively correlated (r2 = 0.913, P < 0.05). Variability in net hepatic glycogen synthesis and the mass of glycogen synthesized via the indirect pathway was reduced in hepatic-denervated dogs (P < 0.05). In conclusion, the glycemic response and rate of net glycogen synthesis during an intraduodenal glucose infusion was no different in hepatic-denervated and -innervated dogs. Net hepatic glucose uptake was sufficient to account for all net hepatic glycogen synthesis and lactate production, consistent with an intrahepatic source of gluconeogenic precursors for glycogen synthesis via the indirect pathway. Hepatic nerves appear responsible for much of the variability in net hepatic glycogen synthesis and in the mass of glycogen synthesized via the indirect pathway in normal dogs.

Amino Acids↗

PubMed2006

Is there an association between sweetened beverages and adiposity?

Four mechanisms were reviewed to explain the possible association between sweetened beverages and increased overweight or obesity: excess caloric intake, glycemic index and glycemic load, lack of effect of liquid calories on satiety, and displacement of milk. The findings were inconsistent across studies. The strongest support was for the excess caloric intake hypothesis, but the findings were not conclusive. Assigning possible links between sweetened beverage consumption and adiposity requires research that compares and contrasts specific mechanisms, especially in populations at risk for obesity, while controlling for likely confounding variables.

Adiposity↗

PubMed2000

Genetically engineered insulin analogs: diabetes in the new millenium.

Tight glucose control is essential to minimize complications in diabetic patients. However, the pharmacokinetic characteristics of the currently available rapid-, intermediate-, and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. Until recently, improvements in insulin formulations were seriously limited as advances were only achieved in insulin purity, species, and characteristics of the retarding agent. The availability of molecular genetic techniques opened new windows to create insulin analogs by changing the structure of the native protein and to improve the therapeutic properties. The first clinically available insulin analog, Lispro, confirmed the hopes by showing that improved glycemic control can be achieved without an increase in hypoglycemic events. This requires, however, optimal basal insulin replacement, either by multiple daily injections of neutral protein Hagedorn (NPH) insulin or by insulin pump. Evidence suggests that short-acting insulin analogs would be better matched by a true basal insulin than by the erratically absorbed and rather short-acting NPH insulin. Therefore, future availability of long-acting analogs raises the hope to realize the true potential benefits of the currently available short-acting analog, Lispro, and of those still awaiting approval. The introduction of new short-acting and the first truly long-acting analogs, the development of analogs with increased stability, less variability and perhaps selective action will help to develop more individualized treatment strategies targeted to specific patient characteristics and to achieve further improvements in glycemic control.

Amino Acid Sequence↗

PubMed2000

Reduced pancreatic B cell compensation to the insulin resistance of aging: impact on proinsulin and insulin levels.

Type 2 diabetes mellitus is associated with insulin resistance, reduced B cell function, and an increase in the proinsulin (PI) to immunoreactive insulin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B cell dysfunction. Normal aging is associated with insulin resistance and reduced B cell function, but it is not known whether changes in PI and the PI/IRI ratio are also a feature of the aging-associated B cell dysfunction. Therefore, we tested whether the aging-associated changes in insulin sensitivity and B cell function result in changes in PI and IRI levels that are proportionate or whether they are disproportionate as in type 2 diabetes. Twenty-six healthy older (mean +/- SEM age, 67 +/- 1 yr) and 22 younger (28 +/- 1 yr) subjects with similar body mass indexes (27.9 +/- 0.6 vs. 26.3 +/- 1.0 kg/m2) were studied. PI was measured by a RIA recognizing both intact PI and its conversion intermediates. The insulin sensitivity index (SI) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucose), and as the acute insulin response to arginine at maximal glycemic potentiation (AIRmax). B cell function was also adjusted for SI based on the known hyperbolic relationship between these two variables. Older and younger subjects had similar fasting glucose (5.3 +/- 0.1 vs. 5.2 +/- 0.1 mmol/L), IRI (83 +/- 8 vs. 76 +/- 9 pmol/L), PI (8.9 +/- 0.8 vs. 10.6 +/- 2.0 pmol/L), and PI/IRI ratio (12.3 +/- 1.3% vs. 13.9 +/- 1.6%; all P = NS) despite a 50% reduction of insulin sensitivity (SI, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol x L; P < 0.001) and in B cell function [SI x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5)(P < 0.001); SI x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); SI x AIRmax, 3.63 +/- 0.53 vs. 6.81 +/- 0.70 x 10(-2) min(-1) (P < 0.001)] in the older subjects. These findings suggest that the B cell dysfunction in older subjects is not associated with disproportionate proinsulinemia. However, in older subjects the B cell response to the insulin resistance of aging is reduced whether measured as fasting levels of PI or IRI or as the acute response to secretagogues. Thus, when examined in terms of the degree of insulin sensitivity, the lower fasting IRI levels in older subjects suggest that the utility of fasting insulin levels as a surrogate measure of insulin resistance in older individuals may be limited.

Adult↗