Frederick Banting's observations leading to the potential for islet neogenesis without transplantation.

On 31 October 1920, Sir Frederick Banting, while preparing for a medical student lecture on diabetes, a topic that he knew little about, learned how pancreatic stones resulted in the formation of new islets of Langerhans. He then scribbled down a potential research study of tying off the ducts of the pancreas and collecting the secretions to improve diabetes. These secretions became known as insulin. A century later, 60 different oral medications and 20 different insulins are available for the treatment of diabetes, yet none stimulate new islet formation. One hundred years later, after the discovery of insulin, more than a dozen research teams from around the world have demonstrated that similar studies to Banting's pancreatic ligation studies have resulted in upregulation of the REG gene. There are now more than 200 publications on the role of Reg gene proteins and shorter Reg peptides in initiating new islet formation islet from exocrine pancreatic ducts and protecting against inflammation to islets resulting in islet death. Human data through Phase 2b in both type 1 and 2 diabetes patients with diabetes for an average of 20 years have demonstrated that the use of a shorter bioactive Reg peptide can generate new endogenous insulin production, resulting in significant reductions in hemoglobin A1C and increases in stimulated C-peptide. The observations of Frederick Banting, one century ago, may now lead to the generation of therapeutics that form new islets without the need for transplantation.

Proposal for generating new beta cells in a muted immune environment for type 1 diabetes.

BACKGROUND: Over the past decade, many immune tolerance agents have shown promise in the non-obese diabetic mouse model for prevention and reversal of type 1 diabetes but have not been successful in clinical trials among recently diagnosed type 1 patients. The trials from decades ago using Cyclosporine A in significantly lower dosages than used for organ transplantation and in similar dosages that have increased T regulatory cell populations in conditions such as atopic dermatitis, demonstrated very high initial insulin-free remission rates when administered immediately after diagnosis. Over time, all newly diagnosed type 1 patients given Cyclosporine A required insulin. Human trials with immune tolerance agents suggest that in addition to an immune tolerance agent, a beta cell regeneration agent may also be necessary to induce long-lasting remission among patients with recent onset type 1 diabetes. METHODS: A randomized, double-blind prospective trial among recent onset type 1 diabetes patients has been designed using Cyclosporine A and a proton-pump inhibitor, which increases gastrin levels and has been shown to work through the Reg receptor to transform pancreatic duct cells into islets.

Distinctions between the islets of mice and men: implications for new therapies for type 1 and 2 diabetes.

OBJECTIVE: To elucidate why diabetes is so difficult to treat despite the present tools and pharmacologic armamentarium and to provide insights into emerging therapies by describing human and rodent data that demonstrates the ability to transform progenitor cells within the adult pancreas into new islets. METHODS: A literature review focused on the distinctions between human and rodent islets. RESULTS: We are beginning to elucidate important differences between the architecture and composition of the islets of Langerhans in humans and rodents. In contrast to rodent islets, human islets are more heterogeneous in cellular composition and have more prominent intra-islet vascularity, with smooth muscle-containing blood vessels that are not present in rodent islets. Some studies report that more than 70% of human beta cells have direct physical contact with other cell types, whereas others describe that smaller human islets possess features more typical of rodents, while larger islets exhibit greater vascularity and a cellular distribution distinct from centrally clustered beta cells surrounded by a mantle of alpha and delta cells found in rodents. CONCLUSIONS: The differences between the islets of mice and men may influence why treatments hailed as reversing diabetes among rodents have not been successfully translated into humans. Increased understanding of the complexities within the human islet may yield unique insights into reversing diabetes in humans.

Distinctions between islet neogenesis and ß-cell replication: implications for reversal of Type 1 and 2 diabetes.

The terms "islet" and "ß-cell" are often used interchangeably, yet islets are highly complex multicellular organelles that contain the insulin-producing ß-cells and four other cells types, all of which play a role in maintaining glucose homeostasis within a very narrow range. Although the formation of new islets in adults is rare, occurring primarily in response to pancreatic injury and major stress to the pancreas, ß-cell replication from existing cells occurs throughout adulthood. An understanding of the regulatory factors controlling pancreatic development has more clearly defined the differences between new islet formation from progenitor cells located throughout the adult pancreas and ß-cell replication occurring within existing islets. The present review sets forth to more clearly distinguish the differences between the postnatal pathways of islet neogenesis and ß-cell replication with a discussion of the potential implications for reversal of Type 1 and 2 diabetic patients using islet neogenesis agents that are now in development. For Type 1 diabetic patients, an immune tolerance agent in conjunction with an islet neogenesis agent may allow achievement of adequate islet mass, perhaps with subsequent potential to withdraw medications. For Type 2 diabetic patients, lifestyle changes and/or medications may sustain the production of new islets and limit the accelerated ß-cell apoptosis characteristic of the condition.

Discovery of a human peptide sequence signaling islet neogenesis.

OBJECTIVE: To identify triggers for islet neogenesis in humans that may lead to new treatments that address the underlying mechanism of disease for patients with type 1 or type 2 diabetes. METHODS: In an effort to identify bioactive human peptide sequences that might trigger islet neogenesis, we evaluated amino acid sequences within a variety of mammalian pancreas-specific REG genes. We evaluated GenBank, the Basic Local Alignment Search Tool algorithm, and all available proteomic databases and developed large-scale protein-to-protein interaction maps. Studies of peptides of interest were conducted in human pancreatic ductal tissue, followed by investigations in mice with streptozocin-induced diabetes. RESULTS: Our team has defined a 14-amino acid bioactive peptide encoded by a portion of the human REG3a gene we termed Human proIslet Peptide (HIP), which is well conserved among many mammals. Treatment of human pancreatic ductal tissue with HIP stimulated the production of insulin. In diabetic mice, administration of HIP improved glycemic control and significantly increased islet number. Bioinformatics analysis, coupled with biochemical interaction studies in a human pancreatic cell line, identified the human exostoses-like protein 3 (EXTL3) as a HIP-binding protein. HIP enhanced EXTL3 translocation from the membrane to the nucleus, in support of a model whereby EXTL3 mediates HIP signaling for islet neogenesis. CONCLUSION: Our data suggest that HIP may be a potential stimulus for islet neogenesis and that the differentiation of new islets is a process distinct from beta cell proliferation within existing islets. Human clinical trials are soon to commence to determine the effect of HIP on generating new islets from one's own pancreatic progenitor cells.

Oral antidiabetic agents in type 2 diabetes.

BACKGROUND: Oral antidiabetic agents differ with regard to mechanisms of action, hemoglobin A(1c)-lowering efficacy, safety, and tolerability. Traditional agents consist of those that enhance insulin secretion (i.e., sulfonylureas and glinides), those that enhance insulin sensitivity (i.e., metformin and the thiazolidinediones), and those that inhibit intestinal carbohydrate absorption (i.e., the alpha-glucosidase inhibitors). New oral agents include the dipeptidyl peptidase-4 (DPP-4) inhibitors, which potentiate the activity of the incretin glucagon-like peptide 1 and enhance glucose-dependent insulin secretion. SCOPE: We review the characteristics of the traditional oral agents and these newer additions to the pharmaceutical armamentarium. Abstracts and original clinical and preclinical reports in the English language were identified for review based on MEDLINE literature searches (1970-2006) and abstract collections from major diabetes meetings. CONCLUSIONS: Traditional oral agents provide significant treatment benefits for diabetic patients, including reduction in risk of microvascular complications. However, most patients with type 2 diabetes do not achieve target glycemic levels with traditional therapies, and these agents are also associated with hypoglycemia, weight gain, and poor tolerability. Oral DPP-4 inhibitors offer the potential for significant improvement in glycemic control without hypoglycemia or weight gain, although long-term durability of glycemic control (>52 weeks) has not been established.

Impact of computer-generated personalized goals on cholesterol lowering.

OBJECTIVES: The National Cholesterol Education Program (NCEP) has enhanced public awareness of the importance of cholesterol in the development of heart disease, yet most patients with cardiovascular disease (CVD) do not know or achieve their low-density lipoprotein cholesterol (LDL-C) goals. This randomized, controlled trial was designed to evaluate the impact of a system that provides uniquely formatted laboratory results to patients with CVD on their changes in LDL-C levels. METHODS: Eighty patients with CVD were randomized to receive standard care or the intervention inclusive of a computer-generated, 11''x17'' color poster depicting an individual's LDL-C status and goals along with personalized steps to aid in goal achievement. Cholesterol profiles were obtained at baseline and 6 months after enrollment. Physicians received standard laboratory reports and were blinded to the randomization. RESULTS: There were no significant differences between patient groups in age, education level, race, baseline cholesterol levels, comorbidities, or percentage of patients in each group who met their NCEP goal at baseline. Patients receiving intervention tools had significant reductions in LDL-C from baseline compared with patients in the control group. Intervention patients who did not meet NCEP goals at baseline had the greatest reduction in LDL-C, with a mean change from baseline of -21.5 mg/dL (P<0.001) whereas standard care patients had no significant change in the LDL-C levels (-4.6 mg/dL, P=0.28). At study close, 73% of intervention patients reported that their posters remained displayed on their refrigerator. CONCLUSION: This unique and personalized intervention resulted in the LDL-C lowering benefit among patients with CVD comparable to that of lipid lowering agents.

Use of the Continuous Glucose Monitoring System to guide therapy in patients with insulin-treated diabetes: a randomized controlled trial.

OBJECTIVE: To show improved glycemic control in patients with insulin-treated diabetes after adjustments to the diabetes management plan based on either continuous glucose monitoring using the Continuous Glucose Monitoring System (CGMS) or frequent self-monitoring of blood glucose (SMBG) using a home blood glucose meter. PATIENTS AND METHODS: From January to September 2000, patients aged 19 to 76 years with insulin-treated diabetes were assigned to insulin therapy adjustments based on either CGMS or SMBG values. At the end of the study, patients in both groups used the CGMS for 3 days; these values were used to calculate measures of hypoglycemia. Repeated-measures analysis of variance with post hoc comparisons were used to test differences in hemoglobin A1c levels and hypoglycemia between the 2 study groups. RESULTS: A total of 128 patients were enrolled in the study. Nineteen discontinued study participation, leaving 51 in the CGMS group and 58 in the SMBG group. No significant differences were noted in demographics or baseline characteristics between the 2 groups. There were no significant differences in hemoglobin A1c levels between the CGMS group and the SMBG group at baseline (9.1% +/- 1.1% vs 9.0% +/- 1.0%, P = .70), and both groups showed statistically significant (P < .001) and similar (P = .95) improvement in hemoglobin A1c levels after 12 weeks of study. However, the CGMS group had a significantly shorter duration of hypoglycemia (sensor glucose, < or = 60 mg/dL) at week 12 of the study (49.4 +/- 40.8 vs 81.0 +/- 61.1 minutes per event, P = .009). CONCLUSION: Use of the CGMS to guide therapy adjustments in patients with insulin-treated diabetes reduces the duration of hypoglycemia compared with therapy adjustments guided by SMBG values alone.

Effect of hyperglycemia on stroke outcomes.

OBJECTIVE: To review published data about the relationship between hyperglycemia and the outcome of patients with stroke. RESULTS: Stroke is the most frequent cause of permanent disability in the Western world and the third leading cause of death among Americans. Each year, more than 500,000 Americans have a cerebrovascular accident. In the medical literature, numerous reports have discussed how hyperglycemia during acute stroke, regardless of a patient's prior diabetes status, has been associated with significantly higher morbidity, higher mortality, longer hospital stays, reduced long-term recovery, and diminished ability to return to work. In the United States alone, an estimated $300 million in additional health-care costs are incurred among hospitalized patients with stroke who also have high blood glucose levels. Treatment of hyperglycemia has safely, successfully, and effectively yielded glucose levels in the normal range in the hospital setting under the direction of specialty physicians and should be implemented in patients with stroke. CONCLUSION: Until convincing randomized prospective trials prove that tight glycemic control does not improve stroke outcomes, the overwhelming preponderance of data suggests that aggressive glucose management should be the standard care in all patients with stroke and hyperglycemia.

Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps.

OBJECTIVE: To assess the effects of adjunctive treatment with pramlintide, an analog of the beta-cell hormone amylin, on 24-h glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions in patients with type 1 diabetes intensively treated with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: In this study, 18 patients (16 of whom could be evaluated) with type 1 diabetes (age 44 +/- 11 years, HbA(1c) 8.2 +/- 1.3% [mean +/- SD]) were given mealtime injections of 30 micro g pramlintide t.i.d. for 4 weeks in addition to their preexisting CSII regimen (16 lispro, 2 regular insulin). Mealtime insulin boluses were reduced by a minimum of 10% during the first 3 days, and re-adjusted thereafter based on clinical judgment. At weeks 0 (baseline), 4 (on treatment), and 6 (2 weeks off treatment), 24-h interstitial glucose concentrations were measured using a continuous glucose monitoring system (CGMS), and postprandial plasma glucose, glucagon, and triglyceride concentrations were measured in response to a standardized test meal. RESULTS: At baseline, patients had excessive 24-h glucose fluctuations, with 59% of the CGMS measurements >140 mg/dl, 13% <80 mg/dl, and only 28% in the euglycemic range (80-140 mg/dl). After 4 weeks on pramlintide, measurements in the hyperglycemic range declined to 48% and measurements within the euglycemic range increased to 37%. This shift from the hyperglycemic to the euglycemic range occurred with a concomitant 17% reduction in mealtime insulin dosages and without relevant increases in measurements below the euglycemic range (15%) or any severe hypoglycemic events. After 4 weeks on pramlintide, postprandial glucose, glucagon, and triglyceride excursions were reduced by approximately 86, approximately 87, and approximately 72%, respectively (incremental areas under the curve, all P < 0.05 vs. baseline). At week 6 (off treatment), the 24-h glucose profile and postprandial glucose, glucagon, and triglyceride excursions approached pretreatment values. CONCLUSIONS: In this study, the addition of pramlintide to insulin therapy reduced excessive 24-h glucose fluctuations as well as postprandial glucose, glucagon, and triglyceride excursions in patients with type 1 diabetes intensively treated with insulin pumps.

Impact of computer-generated personalized goals on HbA(1c).

OBJECTIVE: The public is increasingly aware of the importance of HbA(1c) testing, yet the vast majority of patients with diabetes do not know their HbA(1c) status or goal. We set forth to evaluate the impact of a system that provides uniquely formatted and personalized reports of diabetes status and goals on changes in HbA(1c) levels. RESEARCH DESIGN AND METHODS: A total of 150 patients with diabetes were randomized to receive either standard care or intervention inclusive of a computer-generated 11" x 17" color poster depicting an individual's HbA(1c) status and goals along with personalized steps to aid in goal achievement. All patients enrolled received diabetes education during the 3 months before enrollment. HbA(1c) was performed at baseline and 6 months. RESULTS: At baseline, there were no significant differences between patient groups in terms of age, sex, education level, race, and HbA(1c) or lipid levels. Among patients with baseline HbA(1c) > or =7.0%, there was an 8.6% (0.77% absolute) reduction in HbA(1c) among control subjects compared with a 17.0% (1.69% absolute) decline in the intervention group (P = 0.032). There were no differences between the control and intervention groups with respect to the frequency of patients experiencing any decline in HbA(1c) (63 vs. 69%, P = 0.87); among these patients experiencing a decline, the most substantial reductions were seen with the control group, which had a 13.3% (1.15% absolute) decline compared with the intervention patients, who reduced their HbA(1c) by 24.2% (2.26% absolute reduction; P = 0.0048). At study close, 77% of the patients had their poster displayed on their refrigerator. CONCLUSIONS: This unique and personalized computer-generated intervention resulted in HbA(1c) lowering comparable to that of hypoglycemic agents.

Hemoglobin A1c: need to standardize the term.

PURPOSE: To discuss studies that investigate the understanding of patients with diabetes and the information provided by physicians regarding the terminology and meaning of tests for glycated hemoglobin. FINDINGS: Patients with diabetes seldom know or remember the terminology for glycated hemoglobin assay techniques, even when they are participating in self-monitoring of blood glucose. Physicians use a variety of terms for the glycated hemoglobin test and are not consistent in their terminology. CONCLUSION: One term for glycated hemoglobin assay should be used and promoted by all health-care professionals and patients. Because it is most readily remembered, "A1C" is the preferred lay term.