Showing papers in "Diabetes Care in 1990"

Pathways to Diabetic Limb Amputation: Basis for Prevention

Abstract: We defined the causal pathways responsible for 80 consecutive initial lower-extremity amputations to an extremity in diabetic patients at the Seattle Veterans Affairs Medical Center over a 30-mo interval from 1984 to 1987. Causal pathways, either unitary or composed of various combinations of seven potential causes (i.e., ischemia, infection, neuropathy, faulty wound healing, minor trauma, cutaneous ulceration, gangrene), were determined empirically after a synthesis by the investigators of various objective and subjective data. Estimates of the proportion of amputations that could be ascribed to each component cause were calculated. Twenty-three unique causal pathways to diabetic limb amputation were identified. Eight frequent constellations of component causes resulted in 73% of the amputations. Most pathways were composed of multiple causes, with only critical ischemia from acute arterial occlusions responsible for amputations as a singular cause. The causal sequence of minor trauma, cutaneous ulceration, and wound-healing failure applied to 72% of the amputations, often with the additional association of infection and gangrene. We specified precise criteria in the definition of causal pathway to permit estimation of the cumulative proportion of amputations due to various causes. Forty-six percent of the amputations were attributed to ischemia, 59% to infection, 61% to neuropathy, 81% to faulty wound healing, 84% to ulceration, 55% to gangrene, and 81% to initial minor trauma. An identifiable and potentially preventable pivotal event, in most cases an episode involving minor trauma that caused cutaneous injury, preceded 69 to 80 amputations. Defining causal pathways that predispose to diabetic limb amputation suggests practical interventions that may be effective in preventing diabetic limb loss.

Molecular Biology of Mammalian Glucose Transporters

Abstract: The oxidation of glucose represents a major source of metabolic energy for mammaliancells However, because the plasma membrane is impermeable to polar molecules such as glucose, the cellular uptake of this important nutrient is accomplished by membrane-associated carrier proteins that bind and transfer it across the lipid bilayer Two classes of glucose carriers have been described in mammalian cells: the Na+-glucose cotransporter and the facilitative glucose transporter The Na+-glucose cotransporter transports glucose against its concentration gradient by coupling its uptake with the uptake of Na+ that is being transported down its concentration gradient Facilitative glucose c rriers accelerate the transport of glucose down its concentration gradient by facilitative diffusion, a form of passive transport cDNAs have been isolated from human tissues encoding a Na+-glucose-cotransporter protein and five functional facilitative glucosetransporter isoforms The Na+-glucose cotransporter is expressed by absorptive epithelial cells of the small intestine and is involved in the dietary uptake of glucose The same or a related protein may be responsible for the reabsorption of glucose by the kidney Facilitative glucose carriers are expressed by most if not all cells The facilitative glucose-transporter isoforms have distinct tissue distributions and biochemical properties and contribute to the precise disposal of glucose under varying physiological conditions The GLUT1 (erythrocyte) and GLUT3 (brain) facilitative glucose-transporter isoforms may be responsible for basal or constitutive glucose uptake The GLUT2 (liver) isoform mediates the bidirectional transport of glucose by the hepatocyte and is responsible, at least in part, for the movement of glucose out of absorptive epithelial cells into the circulation in the small intestine and kidney This isoform may also comprise part of the glucosesensing mechanism of the insulin-producing β-cell The subcellular localization of the GLUT4 (muscle/fat) isoform changes in response to insulin, and this isoform is responsible for most of the insulin-stimulated uptake of glucose that occurs in muscle and adipose tissue The GLLJT5 (small intestine) facilitative glucose-transporter isoform is expressed at highest levels in the small intestine and may be involved in the transcellular transport of glucose by absorptive epithelial cells The exon-intron organizations of the human GLUT1 , GLUT2 , and GLUT4 genes have been determined In addition, the chromosomal locations of the genes encoding the Na+-dependent and facilitative glucose carriers have been determined Restriction-fragment-length polymorphisms have also been identified at several of these loci The isolation and characterization of cDNAs and genes for these glucose transporters will facilitate studies of their role in the pathogenesis of disorders characterized by abnormal glucose transport, including diabetes mellitus, the glucose-galactose malabsorption syndrome, and benign renal glycosuria

Development of questionnaire to examine relationship of physical activity and diabetes in Pima Indians.

Abstract: There was a need to design a questionnaire that could accurately assess the activity patterns of Native Americans to evaluate the relationship between physical activity and diabetes. Such a questionnaire was developed and implemented into the data collection scheme of the prospective Pima Indian Study of Arizona. The questionnaire, which assesses historical, past-year, and past-week leisure and occupational activity, was examined in 29 Pima individuals aged 21-36 yr and was shown to be reliable with test-retest correlations (rank-order correlations ranged from 0.62 to 0.96 for leisure and occupational activity). Reproducibility of the past-year leisure physical-activity estimate was determined in 69 participants aged 10-59 yr and was found to be reliable in all age-groups with the exception of the 10- to 14-yr-old age-group (rank-order correlations were 0.31 in the 10- to 14-yr-old age-group compared to 0.88 to 0.92 in those greater than 20 yr of age). Validity of the current-activity section of the questionnaire was demonstrated indirectly through comparisons with activity monitors. The past-week leisure-activity estimate was related to the Caltrac activity monitor counts per hour (rho = 0.62, P less than 0.05, n = 17). In summary, a physical-activity questionnaire has been developed that is both reliable and feasible to use in the Pima Indian population to evaluate the relationship of physical activity to non-insulin-dependent diabetes mellitus.

Insulin and Atheroma: 20-Yr Perspective

Abstract: Many clinical studies have shown an increased insulin response to oral glucose in patients with ischemia of the heart, lower limbs, or brain. Hyperinsulinemia also occurs in patients with angiographically proved atherosclerosis without ischemia and thus appears to be related to arterial disease and not to be a nonspecific response to tissue injury. Fasting insulin levels and insulin responses to intravenous stimuli, including glucose, tolbutamide, and arginine, are normal, suggesting a gastrointestinal factor may be involved in the increased insulin response to oral glucose. In patients with atherosclerosis, insulin sensitivity appears to be normal or enhanced with respect to both glucose and lipid metabolism. Five population studies have shown that insulin responses to glucose are higher in populations at greater risk of cardiovascular disease. Many of the hyperinsulinemic populations also had upper-body obesity, hypertriglyceridemia, lower highdensity lipoprotein (HDL) levels, and hypertension. These prospective studies support an independent association between hyperinsulinemia and ischemic heart disease, although their results differ in detail. Hyperinsulinemia is associated with raised triglyceride and decreased HDL cholesterol levels. Total and lowdensity lipoprotein (LDL) cholesterol is less closely related to hyperinsulinemia. Upper-body adiposity is associated (in separate studies) with coronary heart disease, diabetes, hyperinsulinemia, and hypertriglyceridemia. Insulin and blood pressure are closely related in both normotensive and hypertensive people. Although obesity and diabetes are often found in hypertensive people, hyperinsulinemia also occurs in nonobese nondiabetic hypertensive people. Thus, hyperinsulinemia is closely associated with a cluster of From the Department of Geriatric Medicine, The Queen9s University of Belfast, Belfast, Northern Ireland. Address correspondence and reprint requests to Professor R.W. Stout, Department of Geriatric Medicine, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland. cardiovascular risk factors, i.e., hypertriglyceridemia, low HDL levels, hypertension, hyperglycemia, and upper-body obesity. There is a possibility that insulin has a role in the sex differences in ischemic heart disease incidence and their absence in diabetes, but additional work is required for its clarification. Long-term treatment with insulin results in lipidcontaining lesions and thickening of the arterial wall in experimental animals. Insulin also inhibits regression of diet-induced experimental atherosclerosis, and insulin deficiency inhibits the development of arterial lesions. Insulin stimulates lipid synthesis in arterial tissue; the effect of insulin is influenced by hemodynamic factors and may be localized to certain parts of the artery. In physiological concentrations, insulin stimulates proliferation and migration of cultured arterial smooth muscle cells but has no effect on endothelial cells cultured from large vessels. Insulin also stimulates cholesterol synthesis and LDL binding in both arterial smooth muscle cells and monocyte macrophages. The multiple effects of insulin provide evidence of a potential direct role for this hormone in the development of atherosclerosis. The combination of clinical, epidemiological, and experimental evidence favors a direct role of insulin in the development of atherosclerosis. Insulin may also promote atherogenesis by its effects on lipids and blood pressure. If hyperinsulinemia has a role in atherogenesis, regular physical exercise and avoidance of obesity should be effective in preventing atherosclerosis.

Monomeric insulins and their experimental and clinical implications.

Abstract: Due to the inherent pharmacokinetic properties of available insulins, normoglycemia is rarely, if ever, achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors, among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that, because of more rapid absorption, are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay), ranging from 0.05 to 600% relative to human insulin, were strongly correlated (r = 0.97). In vivo, most of the analogues exhibited approximately 100% activity, explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus, an analogue with reduced binding and clearance gives higher circulating concentrations, counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects, rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly, a more rapid rise in plasma insulin concentration and an earlier hypoglycemic response with the analogues were observed. The monomeric insulin had no lag phase and followed a monoexponential course throughout the absorption process. In contrast, two phases in rate of absorption were identified for the dimer and three for the normal hexameric human insulin. The initial lag phase and the subsequent accelerated absorption of soluble insulin can now be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process. In the light of these results, the effects of insulin concentration, injected volume, temperature, and massage on the absorption process are now also understood.(ABSTRACT TRUNCATED AT 400 WORDS)

Glucose Transport and Glucose Transporters in Muscle and Their Metabolic Regulation

Abstract: Skeletal muscle is the primary tissue responsible for insulin-dependent glucose uptake in vivo; therefore, glucose uptake by this tissue plays an important role in determining glycemia Glucose uptake in muscle occurs by a system of facilitated diffusion involving at least two distinct glucose transporters, GLUT-1 and GLUT-4 Both bind the fungal metabolite and inhibitor of glucose transport cytochalasin B In human skeletal muscle, both types of transporters are detected immunologically, and corresponding mRNA transcripts of both transporter forms are detected In human skeletal muscle cells in culture, in which contamination by other tissues is ruled out, a 50,000-Mr polypeptide is photolabeled with cytochalasin B In rat skeletal muscle, acute treatment with insulin in vivo increases glucose-transport activity and the number of specific cytochalasin B-binding sites at the plasma membrane In mildly diabetic (streptozocin-induced) rats, the number of cytochalasin B-binding sites is decreased in total membranes, and preferentially in the plasma membrane In response to acute insulin treatment, however, there is still recruitment of glucose transporters to the plasma membrane from an intracellular membrane store Hence, migration of transporters does occur in this form of diabetes In L6 muscle cells in culture, acute treatment (1 h) with insulin causes recruitment of glucose transporters to the plasma membrane, and prolonged exposure to insulin or to glucose-deprived medium causes increased expression of GLUT-1 mRNA and GLUT-1 protein Prolonged exposure (24 h) to high glucose in the medium causes a decrease in the number of glucose transporters in the plasma membrane Hence, in those cells the expression of the GLUT-1 glucose transporter is modulated by insulin

Periodontal Disease and NIDDM in Pima Indians

Abstract: The goal of this study was to determine the prevalence and incidence of periodontal disease and its relationship with non-insulin-dependent diabetes mellitus (NIDDM) Two thousand two hundred seventy-three Pima Indians (949 men, 1324 women) aged greater than or equal to 15 yr from the Gila River Indian Community in Arizona were examined between 1983 and 1989 Periodontal disease was diagnosed by tooth loss and by percentage of interproximal crestal alveolar bone loss ascertained from panoramic radiography Subjects with little or no evidence of periodontal disease were classified as nondiseased Thus, the incidence of advanced periodontal disease was determined The age- and sex-adjusted prevalence of periodontal disease at first dental examination was 60% in subjects with NIDDM and 36% in those without Twenty-two new cases developed in a subset of 701 subjects (272 men, 429 women) aged 15-54 yr who initially had little or no evidence of periodontal disease and had at least one additional dental examination The incidence of periodontal disease in this group was similar in men and women (incidence-rate ratio 10, 95% confidence interval [Cl] 05-19, controlled for age and diabetes) Higher age predicted a greater incidence of periodontal disease (chi 2 = 306, df = 3, P less than 0001, controlled for sex and diabetes) The rate of periodontal disease in subjects with diabetes was 26 times (95% Cl 10-66, controlled for age and sex) that observed in those without Although periodontal disease was common in nondiabetic Pima Indians, in whom most of the incident cases occurred, diabetes clearly conferred a substantially increased risk Thus, periodontal disease should be considered a nonspecific complication of NIDDM

Relationship Between Hyperglycemia and Cognitive Function in Older NIDDM Patients

Abstract: The nature and extent of cognitive impairment was examined in 29 healthy elderly subjects (mean age 69.8 yr) with non-insulin-dependent diabetes mellitus (NIDDM) and 30 demographically similar nondiabetic community volunteers (mean age 68 yr). Measures of verbal learning, abstract reasoning, and complex psychomotor functioning were performed more poorly by diabetic than nondiabetic subjects. Conversely, there were no between-group differences in performance on tasks involving pure motor speed and simple verbal abilities. Within the diabetic group, individuals with poorer metabolic control performed more poorly on tasks involving learning, reasoning, and complex psychomotor performance, although this relationship was not evident for simple verbal or motor tasks. These data indicate that older people with NIDDM who are functioning well and perceive themselves as in good health are likely to manifest greater deficits than healthy elderly people in processing complex verbal or nonverbal material. Possible explanatory mechanisms are discussed, and directions for future research are explored.

Effect of Pregnancy on Progression of Diabetic Retinopathy

Abstract: A prospective study was undertaken to determine the effect of pregnancy on diabetic retinopathy. Insulin-taking diabetic women were enrolled; one group was comprised of pregnant women, the other group was comprised of women who were not pregnant. Women were evaluated on referral and again in the postpartum period. The severity of diabetic retinopathy was based on grading of fundus photographs of seven standard photographic fields. The glycosylated hemoglobin, duration of diabetes, current age, diastolic blood pressure, number of past pregnancies, and current pregnancy status were evaluated as risk factors for progression of diabetic retinopathy. After adjusting for glycosylated hemoglobin, current pregnancy was significantly associated with progression (P less than 0.005, adjusted odds ratio 2.3). Diastolic blood pressure had a lesser effect on the probability of progression. The findings from this study indicate that pregnancy and level of glycemia are associated with progression of diabetic retinopathy.

Intracerebral Crises During Treatment of Diabetic Ketoacidosis

Abstract: Sixty-nine instances of intracerebral complications of diabetic ketoacidosis (DKA), including 29 unpublished occurrences, were analyzed to determine predictive factors, the frequency of other disorders resembling cerebral edema, the effectiveness of intervention to reduce intracranial pressure, and whether any etiologic considerations appeared valid. The review failed to implicate rate of hydration, tonicity of administered fluids, rate of correction of glycemia, or use of bicarbonate. Infants and young children (less than 5 yr of age) were disproportionately represented (33%), as were new-onset patients (62%). Approximately 20% of patients were found to have localized basilar edema, hemorrhage, thromboses, or infection by computed tomography scan or on postmortem examination. The histories of 50% of the patients suggested a period of dramatic neurological change preceding respiratory arrest (RA) during which intervention might be effective. Twenty-three patients were treated for increased intracranial pressure before RA; 13 patients survived in an independent functional state, and 3 survived in a severely disabled or vegetative state. Only 3 of the remaining 46 patients survived normally: 2 were untreated and never developed RA, and 1 was given mannitol at the onset of apnea. This review supports close neurological monitoring and intervention to reduce intracranial pressure when there are definite signs of neurological compromise. However, treatment appears to be successful in only 50% of patients who give sufficient warning for such intervention, and they comprised half of the study population. Therefore, prevention of DKA remains the most important goal to avoid intracerebral complications.

Blood Glucose Area Under the Curve: Methodological Aspects

Abstract: To specify the influence of methods used in estimating area under the curve (AUC) and the meaning of total and incremental AUC, 75 glycemic responses to a mixed meal were studied in 75 diabetic patients, 39 with insulin-dependent diabetes mellitus and 36 with non-insulin-dependent diabetes mellitus. AUC was integrated with five computerized methods: polynomial interpolation of third and fourth degree, trapezoidal rule, Simpson's integration, and cubic interpolatory splines. Although these methods gave significantly different results (P less than 0.001), a strong correlation was found between estimations of AUC with different methods (r greater than 0.99, P less than 0.001). In addition, variation between methods was less than or equal to 2%, whereas the coefficient of variation between subjects was 38%. Total AUC was strongly correlated with basal blood glucose value (r = 0.90, P less than 0.001), whereas incremental and positive AUC were not (r = 0.12 and 0.07, respectively, NS). Incremental and positive AUC were strongly correlated with glycemic rise (r = 0.89 and 0.93, respectively, P less than 0.001), whereas total AUC was only slightly so (r = 0.31, P less than 0.01). Incremental and positive AUC gave slightly but significantly different information on glucose response. These results suggest that variations related to the method used in estimating AUC are not clinically relevant and that a simple method such as trapezoidal rule can be used. Total AUC is a descriptive factor related to basal blood glucose value, whereas incremental and positive AUC more accurately describe glycemic response to foods.

Management of Dyslipidemia in NIDDM

Abstract: Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia.

Effect of Metformin on Carbohydrate and Lipoprotein Metabolism in NIDDM Patients

Abstract: The effect of metformin treatment on various aspects of carbohydrate and lipoprotein metabolism has been defined in 12 patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were studied before and after approximately 4 mo of metformin therapy. Treatment was initiated with a single dose of 500 mg/day, increased at weekly intervals, and maintained at a final dose of 2.5 g/day (given at divided intervals) for the last 3 mo of the treatment program. Results demonstrated that both fasting and postprandial glucose concentrations were significantly lower after metformin administration, with the greatest change seen after meals. As a result, the total incremental plasma glucose response above basal measured from 0800 to 1600 after metformin was less than 25% of that seen initially. The improvement in ambient plasma glucose concentration in association with metformin occurred despite a modest but statistically significant decrease in circulating plasma insulin concentration. In addition, insulin-stimulated glucose uptake measured during hyperinsulinemic clamp studies was similar before and after metformin treatment. Furthermore, changes in insulin binding and insulin internalization by isolated monocytes did not correlate with the improvement in glycemic control. Thus, the ability of metformin to lower plasma glucose concentration in NIDDM does not appear to be secondary to an improvement in insulin action. Finally, metformin treatment was associated with a significant (P less than 0.01) decrease in plasma triglyceride concentration and an increase in plasma high-density lipoprotein cholesterol concentration. These results indicate that metformin treatment of patients with NIDDM led to an improvement in both glycemic control and lipoprotein metabolism.

Natural history of beta-cell dysfunction in NIDDM.

Abstract: Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by insulin resistance and beta-cell dysfunction. This review focuses on the beta-cell, what defects occur when and why. Two major anatomic observations have been made in NIDDM. The beta-cell mass is mildly reduced, especially when obesity is taken into account. Also, amyloid deposits are frequently observed in the islets. It is unclear whether these changes are genetically mediated or result secondary to the loss of glucose homeostasis. Many studies have looked at some aspect of insulin secretion in NIDDM, and two types of distinct abnormalities have been described. Early on, there is a marked disruption in pulsatile insulin delivery, which is potentially an important contributor to the insulin resistance. It is unclear whether the loss of pulsatile delivery is acquired or genetically induced. Later, after glucose intolerance has started, several other secretory abnormalities develop coincident with loss of beta-cell glucorecognition. The net result is further deterioration in timing of insulin delivery and postprandial hyperglycemia. A second important consequence of the glucose blindness is that the inherent compensatory beta-cell mechanisms that guard against hyperglycemia are bypassed. We propose that the loss of glucose responsiveness is a direct result of an elevated glucose concentration (so-called glucotoxicity) and have generated substantial data in rat models that support this idea. The logical conclusion is that beta-cell function in NIDDM can be maximized by achieving the best metabolic control possible.

Cellular Mechanism of Action of Metformin

Abstract: Metformin is a hypoglycemic drug effective in the treatment of non-insulin-dependent diabetes mellitus and increasingly used in Canada and Europe. Effects on intestinal glucose absorption, insulin secretion, and hepatic glucose production are insufficient to explain its hypoglycemic action, with most evidence suggesting that the major effect of the drug is on glucose utilization. In vivo and in vitro studies have demonstrated that metformin stimulates the insulin-induced component of glucose uptake into skeletal muscle and adipocytes in both diabetic individuals and animal models. This increase is more significant in diabetic than in nondiabetic animals, suggesting an enhanced action of the drug in the hyperglycemic state. The increase in glucose uptake is also reflected in an increase in the insulin-dependent portion of glucose oxidation. Potential sites of action of metformin are the insulin receptor and the glucose transporters. Although metformin increases insulin binding in various cell types, this effect is not universal and does not correlate with stimulation of glucose utilization. In contrast, direct effects of the drug on the glucose-transport system have been demonstrated. Metformin elevates the uptake of nonmetabolizable analogues of glucose in both nondiabetic rat adipocytes and diabetic mouse muscle. In the latter, the stimulatory effect of the drug is additive to that of insulin. In human and rat muscle cells in culture, metformin increases glucose-analogue transport independently of and additive to insulin, suggesting an insulin-dependent action. Most of these results suggest that the basis for the hypoglycemic effect of this biguanide is probably at the level of skeletal muscle by increasing glucose transport across the cell membrane.

Mutations in insulin-receptor gene in insulin-resistant patients.

Abstract: Defects in insulin-receptor function have been associated with insulin-resistant states such as obesity and non-insulin-dependent diabetes mellitus (NIDDM). Several types of mutations in the insulin-receptor gene have been identified in patients with genetic syndromes of extreme insulin resistance. In some patients, insulin resistance results from a decrease in the number of insulin receptors on the cell surface. In one patient with leprechaunism (leprechaun/Minn-1), there is greater than 90% decrease in the levels of insulin-receptor mRNA. This patient is a compound heterozygote for two mutations in the insulin-receptor gene, both of which act in a cis-dominant fashion to decrease levels of mRNA transcribed from that allele. In one allele, there is a nonsense mutation at codon 897. All 22 exons of the other allele have a normal sequence, so that the mutation in this allele appears to map outside the coding sequence of the gene. Impaired insertion in the plasma membrane also causes insulin resistance. In two sisters (patients A-5 and A-8) with type A extreme insulin resistance, there is an 80-90% decrease in the number of insulin receptors expressed on the surface of their cells. Both sisters, whose parents are first cousins, are homozygous for a point mutation in which valine is substituted for phenylalanine at position 382 in the alpha-subunit of the insulin receptor. This mutation retards the posttranslational processing of the receptor and impairs the transport of receptors to the cell surface. Another patient with leprechaunism (leprechaun/Ark-1) is a compound heterozygote with two different mutant alleles of the insulin-receptor gene. In the allele derived from the father, there is a nonsense mutation at codon 672 that truncates the insulin receptor by deleting the COOH-terminal of the alpha-subunit and the entire beta-subunit. This truncated receptor, lacking a transmembrane domain, appears not to be expressed at the plasma membrane. In leprechaun/Ark-1, there is a missense mutation in the allele of the insulin-receptor gene derived from the mother. This point mutation results in substitution of glutamic acid for lysine at position 460 in the COOH-terminal half of the alpha-subunit. This mutation increases receptor affinity and impairs the ability of acid pH to dissociate insulin from the receptor within the endosome. There is a defect in recycling the receptor back to the plasma membrane associated with this defect. This results in an accelerated rate of receptor degradation and a consequent decrease in the number of receptors on the cell surface in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Factors Associated With Avoidance of Severe Complications After 25 Yr of IDDM: Pittsburgh Epidemiology of Diabetes Complications Study I

Abstract: To identify characteristics associated with long-term avoidance of insulin-dependent diabetes mellitus (IDDM) complications, subjects taking part in an epidemiologic natural history study of childhood-onset IDDM, with a duration of disease greater than or equal to 25 yr, were studied. Nineteen percent of 175 subjects had avoided overt nephropathy, definite cardiovascular and peripheral vascular disease, clinical neuropathy, and proliferative retinopathy. Approximately half of the nonrenal complications occurred in the absence of renal disease. Subjects free of these advanced complications were characterized by a longer duration of disease (P less than 0.05), better lipid profile and blood pressure (P less than 0.01), and considerably lower glycosylated hemoglobin levels (P less than 0.001). Health-related behaviors, including recent medical contact, regular glucose monitoring, physical activity in youth, and avoidance of cigarette smoking, did not relate to complication status, although regular (at least weekly) alcohol consumption was more prevalent (P less than 0.05) in those without complications. We conclude that a lower mean glycosylated hemoglobin level is strongly related to the avoidance of all IDDM complications.

Molecular Physiology of Glucose Transporters

Abstract: Molecular cloning of cDNA encoding the human erythrocyte facilitated-diffusion glucose transporter (GT) has elucidated its structure and has permitted a careful study of its tissue distribution and of its involvement in processes such as insulin-stimulated glucose uptake by adipose cells or transformation-induced increase in glucose metabolism. An important outcome of these studies was the discovery that additional isoforms of this transporter were expressed in a tissue-specific manner; these comprise a family of structurally and functionally related molecules. Their tissue distribution, differences in kinetic properties, and differential regulation by ambient glucose and insulin levels suggest that they play specific roles in the control of glucose homeostasis. Herein, we will discuss the structure of three members of the GT family: erythroid/brain GT, liver GT, and adipose cell/muscle GT. In the light of their tissue-specific expression, kinetic parameters, and susceptibility to insulin action, we discuss their possible specific functions.

Intensive Insulin Therapy for Treatment of Type I Diabetes

Abstract: Intensive insulin therapy is best defined as a comprehensive system of diabetes management with the patient and management team as partners. The system is directed at improvement of glycemia and patient well-being. Glycemic targets should be individually defined. Frequent self-monitoring of blood glucose, probably at least four times per day, is essential for meticulous control. The benefits include improved psychosocial functioning and the potential of lessening the risks of chronic complications of diabetes. The risks relate to problems associated with hypoglycemia, which are increased if meticulous glycemic control is sought. One of the important elements of intensive therapy is a multiple-component insulin program designed to provide effective insulinemia coinciding with each major meal and continuous basal insulinemia throughout the 24-h day. This may be achieved with continuous subcutaneous insulin infusion (CSII) or multiple injections with various insulin regimens, although CSII may offer real advantages in terms of the pharmacokinetics of insulin delivery. Other pharmacokinetic issues to be considered involve selection of injection sites, timing of premeal insulin, and mixing insulins. Many studies have shown that, albeit with effort, excellent glycemic control can be achieved by various intensive insulin-therapy regimens. The implementation of a program of intensive therapy involves patient self-management in terms of altering insulin dosages, food intake, and/or activity in an attempt to achieve the target level of glycemia selected. In motivated patients willing to embark on such a course of therapy, intensive insulin therapy can be worthwhile. It should be considered for all patients with type I (insulin-dependent) diabetes mellitus.

Scope and heterogeneous nature of MODY.

Abstract: This review summarizes aspects of the phenotypic expression, natural history, recognition, pathogenesis, and heterogeneous nature of maturity-onset diabetes of the young (MODY), which is inherited in an autosomal-dominant pattern. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among White pedigrees. In MODY patients with low insulin responses, there are delayed and decreased insulin and C-peptide secretory responses to glucose from childhood or adolescence even before glucose intolerance appears, which may represent the basic genetic defect. When followed for decades, nondiabetic siblings have normal insulin responses. The fasting hyperglycemia of some MODY patients has been treated successfully with sulfonylureas for up to 30 yr. In a few patients, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they resemble those of early insulin-dependent diabetes mellitus. The progression of the insulin secretory defect over time distinguishes between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose, despite glucose intolerance and fasting hyperglycemia similar to that seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta-cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, a structurally abnormal mutant insulin molecule that is biologically ineffective is secreted. No associations have been found between specific HLA antigens and MODY in White, Black, and Asian pedigrees. Linkage studies of the insulin gene, insulin-receptor gene, erythrocyte/HepG2 glucose-transporter locus, and apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional non-insulin-dependent diabetes mellitus. Because of autosomal-dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in non-insulin-dependent diabetes mellitus, including the use of genetic linkage strategies to identify diabetogenic genes.

Comparison of Quantitative Sensory-Threshold Measures for Their Association With Foot Ulceration in Diabetic Patients

Abstract: We compared the accuracy of cutaneous pressure perception-threshold measurements with that of other sensory-threshold measurements for detecting diabetic foot ulcer patients. Three hundred fourteen non-insulin-dependent diabetic patients were studied, of whom 91 had either a current foot ulcer or a history of foot ulceration. Foot ulcer patients had much higher pressure perception thresholds at the hallux than those without foot ulcers (mean +/- SE 4.63 +/- 0.05 vs. 3.54 +/- 0.04 U, P less than 0.001). The magnitude of association was higher than that for vibration thresholds and markedly greater than those for cool and warm thresholds. Pressure thresholds were highly accurate for identifying foot ulcer patients. At a threshold level of 4.21 U, the sensitivity was 0.84, with a specificity of 0.96. At similar sensitivities for vibration and thermal thresholds, specificities were lower. Foot ulceration and cutaneous pressure perception threshold are strongly associated. Pressure-threshold measurements are extremely accurate and perform at least as well as other quantitative sensory tests in identifying foot ulcer patients. Assessment of the foot pressure threshold may have promise as a simple and inexpensive method for detecting diabetic patients at risk for foot ulcers.

Ion channels and insulin secretion.

Abstract: We review the role of ion channels in regulating insulin secretion from pancreatic beta-cells. By controlling ion permeability, ion channels at the membrane play a major role in regulating both electrical activity and signal transduction in the beta-cell. A proximal step in the cascade of events required for stimulus-secretion coupling is the closure of ATP-sensitive K+ channels, resulting in cell depolarization. Of particular relevance is the finding that this channel is directly regulated by a metabolite of glucose, which is the primary insulin secretagogue. In addition, this channel, or a closely associated protein, contains the sulfonylurea-binding site. Another K+ channel, the Ca2(+)-activated K+ channel, may be involved in cell repolarization to create homeostasis. Voltage-dependent Ca2+ channels are activated by cell depolarization and regulate Ca2+ influx into the cell. By controlling cytosolic free-Ca2+ levels ([Ca2+]i), these channels play an important role in transducing the initial stimulus to the effector systems that modulate insulin secretion. The link between a rise in [Ca2+]i and the terminal event of exocytosis is the least-understood aspect of stimulus-secretion coupling. However, phosphorylation studies have identified substrate proteins that may correspond to those involved in smooth muscle contraction, suggesting an analogy in the processes of stimulus secretion and excitation contraction. The advent of new methodology, particularly the patch-clamp technique, has fostered a more detailed characterization of the beta-cell ion channels. Furthermore, biochemical and molecular approaches developed for the structural analysis of ion channels in other tissues can now be applied to the isolation and characterization of the beta-cell ion channels. This is of particular significance because there appear to be tissue-specific variations in the different types of ion channels. Given the importance of ion channels in cell physiology, a knowledge of the structure and properties of these channels in the beta-cell is required for understanding the abnormalities of insulin secretion that occur in non-insulin-dependent diabetes mellitus. Ultimately, these studies should also provide new therapeutic approaches to the treatment of this disease.

Second Messengers of Insulin Action

Abstract: Despite significant advances in past years on the chemistry and biology of insulin and its receptor, the molecular events that couple the insulin-receptor interaction to the regulation of cellular metabolism remain uncertain. Progress in this area has been complicated by the pleiotropic nature of the actions of insulin. These most likely involve a complex network of pathways resulting in the coordination of mechanistically distinct cellular effects. Because the well-recognized mechanisms of signal transduction (i.e., cyclic nucleotides, ion channels) appear not to be central to insulin action, investigators have searched for a novel second-messenger system. A low-molecular-weight substance has been identified that mimics certain actions of insulin on metabolic enzymes. This substance has an inositol glycan structure, and is produced by the insulin-sensitive hydrolysis of a glycosylphosphatidylinositol in the plasma membrane. This hydrolysis reaction, which is catalyzed by a specific phospholipase C, also results in the production of a structurally distinct diacylglycerol that may selectively regulate one or more of the protein kinases C. The glycosyl-phosphatidylinositol precursor for the inositol glycan enzyme modulator is structurally analogous to the recently described glycosyl-phosphatidylinositol membrane protein anchor. Preliminary studies suggest that a subset of proteins anchored in this fashion may be released from cells by a similar insulin-sensitive phospholipase-catalyzed reaction. Future efforts will focus on the precise role of the metabolism of glycosyl phosphatidylinositols in insulin action.

Randomized Prospective Study of Self-Management Training With Newly Diagnosed Diabetic Children

Abstract: This study was designed to evaluate the effects of a self-management training (SMT) program on metabolic control of children with insulin-dependent diabetes mellitus (IDDM) in the first 2 yr after diagnosis. After standard in-hospital diabetes education, 36 children (mean age 9.3 yr, range 3–16 yr) were randomized to conventional follow-up, conventional and supportive counseling (SC), or conventional and SMT, which emphasized use of data obtained from self-monitoring of blood glucose. SC and SMT interventions consisted of seven outpatient sessions with a medical social worker during the first 4 mo after diagnosis and booster sessions at 6 and 12 mo postdiagnosis. Groups were similar with respect to age, sex, body mass index, socioeconomic status, C-peptide, and severity of illness at diagnosis. Metabolic control, measured quarterly by glycosylated hemoglobin (HbA1), improved substantially in all three treatment groups during the first 6 mo. SMT patients had significantly lower HbA1 levels than conventional patients at 1 yr ( P < 0.01) and 2 yr ( P < 0.05) postdiagnosis. SMT patients also had lower HbA1 levels than SC patients, but this did not reach statistical significance. The lower HbA1 levels of SMT patients were not explained by severity of illness at diagnosis, or insulin dose, body mass index, and C-peptide levels at 2 yr. These results suggest that an SMT program during the first few months after diagnosis helps avoid the deterioration in metabolic control often seen in children with IDDM between 6 and 24 mo after diagnosis.

Lessons Learned From Molecular Biology of Insulin-Gene Mutations

Abstract: Studies on naturally occurring and man-made mutations in the insulin gene have provided new insights into insulin biosynthesis, action, and metabolism. Ten families have been identified in which one or more members have single-point mutations in their insulin genes that result in amino acid substitutions within the proinsulin molecule. Six of these cause the secretion of biologically defective insulin molecules due to changes within the A or B chains. Replacing A3-Val with Leu, B24-Phe with Ser, or B25-Phe with Leu results in molecules that have essentially normal immunoreactivity but greatly reduced insulin-receptor-binding potency. Individuals with these mutations have a syndrome of mild diabetes or glucose intolerance, which is inherited in an autosomal-dominant mode and is associated with hyperinsulinemia and altered insulin-C-peptide ratios. Although affected individuals are heterozygous and coexpress both normal and abnormal molecules, the elevated circulating insulin consists mainly of the biologically defective form, which accumulates because it fails to be rapidly metabolized via receptor-mediated endocytosis. Four additional families have mutations that are associated with relatively asymptomatic hyperproinsulinemia. A point mutation affecting proinsulin occurs in 3 of the 4 families, leading to replacement of Arg-65 by His, which prevents recognition of the C-peptide-A-chain dibasic cleavage site by the appropriate (β-cell processing protease and results in the circulation of a type II proinsulin intermediate form (des 64, 65 HPI). Members of a fourth family with hyperproinsulinemia have a substitution of B10-His with Asp, resulting in a proinsulin that exhibitsmarkedly altered subcellular sorting behavior. A significant proportion of the newly synthesized Asp-10 proinsulin is secreted in an unprocessed form via an unregulated or constitutive secretory pathway. This syndrome has been modeled in transgenic mice by introduction of this abnormal gene into the germ line, resulting in its expression at high levels along with the normal mouse insulin genes in the β-cells. These animals have not only reproduced the hyperproinsulinemia syndrome, thus allowing us to examine its mechanism in considerable detail, but have also provided opportunities to examine other aspects of insulin-gene expression. Various molecular expression techniques are now available that allow normal or mutated insulin genes to be expressed via transfection of DNA in cultured cells, injections of in vitro-generated mRNA into Xenopus oocytes, or translation of mRNA in reticulocyte cell-free systems so that their altered properties can be assessed. Application of these and other molecular biological techniques to the expression of naturally occurring mutant proinsulins and others made in the laboratory has provided new forms of insulin for therapy of diabetes and a deeper understanding of the mechanisms of biosynthesis, intracellular sorting, processing, and secretion of insulin under normal and abnormal conditions.

Physiology and pathophysiology of insulin secretion.

Abstract: Mechanisms by which various classes of extracellular signals regulate insulin secretion are discussed regarding their cellular and molecular actions. Under physiological circumstances, the small postprandial changes in plasma glucose concentrations (approximately 4.4-6.6 mM) primarily serve as a conditioned modifier of insulin secretion and dramatically alter the responsiveness of islets to a combination of neurohormonal agonists. These agonists have two functions. Cholecystokinin (CCK) and acetylcholine activate the hydrolysis of polyphosphoinositides, and gastric inhibitory polypeptide (GIP) and glucagonlike peptide 1 activate adenylate cyclase. These two functional classes of neurohumoral agonists act synergistically to enhance insulin secretion when plasma glucose is greater than 6.0 mM but not when it is less than or equal to 4 mM. On the other hand, an increase in plasma glucose concentration to 8-10 mM induces an increase in insulin secretory rate in the absence of any of the neurohormonal agonists. Remarkably, high glucose leads to an increase in the same intracellular signals, as does a combination of acetylcholine and GIP. On the basis of these data, a model of how insulin secretion is regulated under physiological circumstances is proposed. This model emphasizes that the regulation of insulin secretion occurs in three stages: cephalic, early enteric, and later enteric. In this view, the crucial event occurring during the first two phases is the agonist-induced, translocation of protein kinase C (PKC) to the plasma membrane under conditions in which an increase in Ca2+ influx does not occur. PKC is now in a cellular location and a Ca2(+)-sensitive conformation such that an increase in Ca2+ influx rate occurring during the third phase leads to its immediate activation and an enhanced rate of insulin secretion. Furthermore, under physiological circumstances, an optimal insulin secretory response is dependent on a correct temporal pattern of signals arising from neural and enteric sources. If this pattern is deranged, an abnormal pattern of insulin secretion is observed. An important new insight is provided by the observation that agonists (e.g., CCK or acetylcholine) that act to stimulate the hydrolysis of phosphatidylinositides, when acting for a short period (10-20 min), induce an enhanced responsiveness of islets to glucose, i.e., proemial sensitization. However, when acting unopposed for several hours, these agonists will induce a time-dependent suppression of responsiveness to glucose and other agonists. The latter observation implies that optimal insulin secretion is dependent on periodic rather than a continuous exposure to the correct pattern of extracellular signals.(ABSTRACT TRUNCATED AT 400 WORDS)

Regulation of Glucose-Transporter Gene Expression In Vitro and In Vivo

Abstract: Understanding of the fundamental mechanisms underlying the complex regulation of glucose homeostasis has been dramatically transformed recently by the realization that glucose transport in mammalian tissues is mediated by a family of structurally related but genetically distinct glucose-transporter proteins. The regulatory factors and intracellular signaling pathways that influence expression of the genes encoding these proteins are just being identified. Factors that regulate glucose-transporter gene expression in vitro include oncogenes, growth factors, insulin, oral hypoglycemic agents, vanadate, glucocorticoids, ambient glucose levels, and the state of cellular differentiation. In vivo, glucose-transporter gene expression in adipose cells, skeletal muscle, and liver is markedly affected by various altered nutritional and metabolic states. Recent studies have demonstrated that two glucose transporters expressed in the same tissue may be regulated differently in response to the same metabolic perturbation. Furthermore, transporter regulation appears to be tissue specific. These observations lay the groundwork for future studies aimed at unraveling the functional roles of the individual transporter species in different tissues, the molecular processes involved in regulating the expression of these genes, and the impact of dysregulated glucose-transporter gene expression in the pathogenesis of insulin-resistant states such as diabetes.

Insulin Use in NIDDM

Abstract: The effects of insulin treatment on the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM) are reviewed herein. Short-term studies indicate variable and partial reduction in excessive hepatic glucose output, decrease in insulin resistance, and enhancement of beta-cell function. These beneficial actions may be due to a decrease in secondary glucose toxicity rather than a direct attack on the primary abnormality. Insulin should be used as initial treatment of new-onset NIDDM in the presence of ketosis, significant diabetes-induced weight loss (despite residual obesity), and severe hyperglycemic symptoms. In diet-failure patients, prospective randomized studies comparing insulin to sulfonylurea treatment show approximately equal glycemic outcomes or a slight advantage to insulin. A key goal of insulin therapy is to normalize the fasting plasma glucose level. In contrast to the conventional use of morning injections of intermediate- and long-acting insulin, preliminary studies suggest potential advantages of administering the same insulins only at bedtime. Obese patients may require several hundred units of insulin daily and still not achieve satisfactory control. In some, addition of a sulfonylurea to insulin may reduce hyperglycemia, the insulin dose, or both. However, long-term benefits from such combination therapy remain to be demonstrated conclusively. Established adverse effects of insulin treatment in NIDDM are hypoglycemia, particularly in the elderly, and weight gain. Self-monitoring of blood glucose can identify patients in whom excessive weight gain is caused by subtle hypoglycemia. Whether insulin causes weight gain by direct effects on appetite or energy utilization remains controversial. A potential adverse effect of insulin has been suggested by epidemiological studies showing associations between hyperinsulinemia or insulin resistance and increased risk for coronary artery disease, stroke, and hypertension. Although potential mechanisms for an atherogenic action of insulin exist, current evidence does not prove cause and effect and does not warrant withholding insulin therapy (or compromising on dosage) when it is needed.

Impact of Glucose Self-Monitoring on Non-lnsulin-Treated Patients With Type II Diabetes Mellitus: Randomized Controlled Trial Comparing Blood and Urine Testing

Abstract: The goal of this study was to compare the relative efficacy and cost of self-monitoring of blood glucose (SMBG) with routine urine testing in the management of patients with type II (non-insulin-dependent) diabetes mellitus not treated with insulin. Fifty-four patients with type II diabetes mellitus, not treated with insulin, who had inadequate glucose control on diet aloneor diet and oral hypoglycemic agents were studied. Patients performed SMBG or urine glucose testing as part of a standardized treatment program that also included diet and exercise counseling. During the 6-mo study, both the urine-testing and SMBG groups showed similar improvement in glycemic control; within each group, there were significant improvements in fasting plasma glucose (reduction of 1.4 ± 3.2 mM, P P P > 0.86), glycosylated hemoglobin ( P > 0.95), or weight ( P

Prevalence of diabetes and impaired glucose tolerance in elderly subjects and their association with obesity and family history of diabetes.

Abstract: The goal of this study was to investigate the prevalence of impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) in elderly subjects and their association with obesity, central obesity, and a family history of diabetes. A representative population sample of 1300 subjects (471 men, 829 women) aged 65-74 yr participated in the study. The participation rate was 71%. The prevalence rates of previously and newly diagnosed NIDDM and IGT, based on a history of diabetes and an oral glucose tolerance test, were 8.7, 7.0, and 17.8% in men and 11.7, 7.1, and 19.1% in women. Thus, 33.8% of men and 37.9% of women had abnormal glucose tolerance according to World Health Organization criteria. Obesity (body mass index greater than or equal to 27 kg/m2 in men and greater than or equal to 25 kg/m2 in women) and central obesity (waist-hip ratio greater than or equal to 0.98 in men and greater than or equal to 0.89 in women) doubled the prevalence of IGT or NIDDM. The combination of obesity and a family history of diabetes was associated with a more marked increase in the prevalence of IGT or NIDDM in men than in women. Simultaneous presence of obesity, central obesity, and a family history of diabetes was associated with a threefold increase in the prevalence of IGT or NIDDM (65.4 vs. 24.1% in men, 52.8 vs. 19.6% in women, P less than 0.001). The major risk factors for NIDDM, e.g., obesity, central fat distribution, and a family history of diabetes, explained 10% of the variance in 2-h glucose values in multiple regression analysis. In conclusion, the prevalence of IGT and NIDDM was high in elderly subjects. Although obesity, central fat distribution, and a family history of diabetes were significantly associated with the increased prevalence of IGT or NIDDM, they explained only a minor proportion of the variance in 2-h glucose values.