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Fulltext Current therapies and targets for type 2 diabetes mellitus

Chellappan DK, Yap WS, Bt Ahmad Suhaimi NA, Gupta G, Dua K

Panminerva Med, 2018 Sep;60(3):117-131.
PMID: 29696964 DOI: 10.23736/S0031-0808.18.03455-9

The prevalence of type 2 diabetes mellitus (T2DM) has been increasing at an alarming rate. With an increased understanding of the pathophysiology and pathogenesis of T2DM, various new therapeutic options have been developed to target different key defects in T2DM. Incremental innovations of existing therapies either through unprecedented drug combinations, modified drug molecules, or improved delivery systems are capable to nullify some of the undesirable side effects of traditional therapies as well as to enhance effectiveness. The existing administration routes include inhalation, nasal, buccal, parenteral and oral. Newer drug targets such as protein kinase B (Akt/PKB), AMP-activated protein kinase (AMPK), sirtuin (SIRT), and others are novel approaches that act via different mechanisms and possibly treating T2DM of distinct variations and aetiologies. Other therapies such as endobarrier, gene therapy, and stem cell technology utilize advanced techniques to treat T2DM, and the potential of these therapies are still being explored. Gene therapy is plausible to fix the underlying pathology of T2DM instead of using traditional reactive treatments, especially with the debut of Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein9 (CRISPR-Cas9) gene editing tool. Molecular targets in T2DM are also being extensively studied as it could target the defects at the molecular level. Furthermore, antibody therapies and vaccinations are also being developed against T2DM; but the ongoing clinical trials are relatively lesser and the developmental progress is slower. Although, there are many therapies designed to cure T2DM, each of them has their own advantages and disadvantages. The preference for the treatment plan usually depends on the health status of the patient and the treatment goal. Therefore, an ideal treatment should take patient's compliance, efficacy, potency, bioavailability, and other pharmacological and non-pharmacological properties into account.

Matched MeSH terms: Insulin/administration & dosage
Partial remission in type 1 diabetes and associated factors: Analysis based on the insulin dose-adjusted hemoglobin A1c in children and adolescents from a regional diabetes center, Auckland, New Zealand

Chiavaroli V, Derraik JGB, Jalaludin MY, Albert BB, Ramkumar S, Cutfield WS, et al.

Pediatr Diabetes, 2019 11;20(7):892-900.
PMID: 31237756 DOI: 10.1111/pedi.12881

BACKGROUND: Partial remission (PREM) by the insulin dose-adjusted HbA1c (IDAA1c) method has not been evaluated for the combined associations of ethnicity and socioeconomic status in children and adolescents with type 1 diabetes (T1D).
OBJECTIVE: To investigate prevalence and predictors of PREM defined by IDAA1c.
METHODS: Six hundred fourteen of 678 children (aged <15 years) with new-onset T1D (2000-2013) from a regional pediatric diabetes service (Auckland, New Zealand).
RESULTS: Overall rate of PREM at 3 months was 42.4%, and lower in Māori/Pacific children (28.6%; P = .006) and those of other ethnicities (28.8%; P = .030) compared with New Zealand Europeans (50.4%). Comparing the most and least deprived socioeconomic quintiles, the odds of PREM were lower among the most deprived (adjusted odds ratio [aOR] 0.44; P = .019). Lower rates of PREM were seen in children aged 0 to 4.9 years (23.8%) and 10 to 14 years (40.9%) than in children aged 5 to 9.9 years (57.4%; P

Matched MeSH terms: Insulin/administration & dosage*
Transdermal insulin delivery with microwave and fatty acids as permeation enhancers

Harjoh N, Wong TW, Caramella C

Int J Pharm, 2020 Jun 30;584:119416.
PMID: 32423875 DOI: 10.1016/j.ijpharm.2020.119416

Inhaled/oral insulin have been investigated as an alternative to injectable insulin, but are met with unsatisfactory outcomes. Transdermal administration bears several advantages unmet by inhalation/oral delivery, but macromolecular drugs permeation is poor. This study explored microwave to elicit transdermal insulin permeation, and compared against conventional permeation enhancers (fatty acids) in vitro/in vivo. The transdermal insulin permeation was promoted by microwave (2450 MHz/1 mW) > oleic acid (monounsaturated) ~ linoleic acid (double unsaturated bonds). The linolenic acid (triple unsaturated bonds) or combination of microwave/fatty acid reduced skin insulin permeation. Transdermal insulin permeation enhancement was attributed to epidermal lipid bilayer fluidization (CH) and corneocyte shrinkage due to keratin condensation (OH/NH, CO), which had aqueous pore enlarged to facilitate insulin transport. Its reduction by linolenic acid, a molecularly larger and rigid fatty acid with higher surface tension, was due to reduced fatty acid permeation into epidermis and minimal skin microstructural changes. The oleic acid, despite favoured skin microstructural changes, did not provide a remarkably high insulin permeation due to it embedded in skin as hydrophobic shield to insulin transport. Microwave penetrates skin volumetrically with no chemical residue retention. It alone promoted insulin absorption and sustained blood glucose level reduction in vivo.

Matched MeSH terms: Insulin/administration & dosage*
Fulltext Worldwide Injection Technique Questionnaire Study: Injecting Complications and the Role of the Professional

Frid AH, Hirsch LJ, Menchior AR, Morel DR, Strauss KW

Mayo Clin Proc, 2016 Sep;91(9):1224-30.
PMID: 27594186 DOI: 10.1016/j.mayocp.2016.06.012

From February 1, 2014, through June 30, 2015, 13,289 insulin-injecting patients from 423 centers in 42 countries participated in one of the largest surveys ever performed in diabetes. The first results of this survey are published elsewhere in this issue. Herein we report that the most common complication of injecting insulin is lipohypertrophy (LH), which was self-reported by 29.0% of patients and found by physical examination in 30.8% by health care professionals (HCPs). Patients with LH consumed a mean of 10.1 IU more insulin daily than patients without LH. Glycated hemoglobin levels averaged 0.55% higher in patients with vs without LH. Lipohypertrophy was associated with higher rates of unexplained hypoglycemia and glycemic variability as well as more frequent diabetic ketoacidosis, incorrect rotation of injection sites, use of smaller injection zones, longer duration of insulin use, and reuse of pen needles (each Pinsulin injection practices.
Study sites: 423 centers in 42 countries (Malaysia contributed 51 patients from two hospital study sites)

Matched MeSH terms: Insulin/administration & dosage*
Low prevalence of autoimmune diabetes markers in a mixed ethnic population of Singaporean diabetics

Todd AL, Ng WY, Lui KF, Thai AC

Intern Med J, 2004 Jan-Feb;34(1-2):24-30.
PMID: 14748910 DOI: 10.1111/j.1444-0903.2004.00482.x

BACKGROUND: Circulating antibodies to glutamic acid decarboxylase (GADab) and tyrosine phosphatase-like molecule IA-2 (IA-2ab) are major indicators for auto-immune destruction of pancreatic islet cells. They identify a majority of Caucasians with type 1 diabetes and approximately 50% of Asians, providing evidence of an idiopathic aetiology in the latter. The present study investigated these autoantibodies in a mixed ethnic group.
METHODS: Hospital clinic patients with clinically defined type 1 (n = 93) and type 2 (n = 300) diabetes and representing Singapore's major ethnic groups--Chinese, Indians and Malays--were studied. GADab and IA-2ab frequencies, and association of autoimmunity status with clinical and biochemical profiles were analysed.
RESULTS: Radio-immunoprecipitation assays detected either or both antibodies (seropositivity) in 41.9% of subjects with type 1 diabetes. GADab was detected in 36.6% and IA-2ab in 23.7% of type 1 diabetics. Prevalence of IA-2ab showed a reduction in frequency with disease duration (P = 0.026). In clinical type 2 diabetics, seropositivity was 10.0% with higher frequency in Malays (17.5%) than Chinese (9.7%) and Indians (4.5%). Multivariate analysis revealed that low fasting C-peptide was associated with seropositivity (odds ratio (OR) = 0.15; 95% confidence interval (CI) = 0.04-0.58). A significant relationship (OR = 13.5; 95% CI = 5.0-36.7) between insulin requirement and duration (>5 years) was also revealed. In patients with type 2 diabetes there was a trend of gradual progression to insulin dependency. However, there was considerable variation in body mass index between ethnic subgroups of type 2 diabetics, particularly for Chinese (mean (SD) = 26.0 (4.7)) and Malays (mean (SD) = 29.2 (5.9); P < 0.001).
CONCLUSIONS: Presence of both antibodies in our mixed ethnic group of type 1 diabetes patients was much lower than in Caucasians. Significant numbers of patients were seronegative for antibodies. Influences due to ethnicity and adiposity would require further investigations.

Matched MeSH terms: Insulin/administration & dosage
Fulltext Usability and utility evaluation of the web-based "Should I Start Insulin?" patient decision aid for patients with type 2 diabetes among older people

Lee YK, Lee PY, Ng CJ, Teo CH, Abu Bakar AI, Abdullah KL, et al.

Inform Health Soc Care, 2018 Jan;43(1):73-83.
PMID: 28139158 DOI: 10.1080/17538157.2016.1269108

This study aimed to evaluate the usability (ease of use) and utility (impact on user's decision-making process) of a web-based patient decision aid (PDA) among older-age users. A pragmatic, qualitative research design was used. We recruited patients with type 2 diabetes who were at the point of making a decision about starting insulin from a tertiary teaching hospital in Malaysia in 2014. Computer screen recording software was used to record the website browsing session and in-depth interviews were conducted while playing back the website recording. The interviews were analyzed using the framework approach to identify usability and utility issues. Three cycles of iteration were conducted until no more major issues emerged. Thirteen patients participated: median age 65 years old, 10 men, and nine had secondary education/diploma, four were graduates/had postgraduate degree. Four usability issues were identified (navigation between pages and sections, a layout with open display, simple language, and equipment preferences). For utility, participants commented that the website influenced their decision about insulin in three ways: it had provided information about insulin, it helped them deliberate choices using the option-attribute matrix, and it allowed them to involve others in their decision making by sharing the PDA summary printout.
Study site: urban tertiary teaching hospital outpatient clinic in Malaysia (primary care clinic, University Malaya Medical Centre, UMMC, Kuala Lumpur, Malaysia)

Matched MeSH terms: Insulin/administration & dosage*
Blood glucose lowering property of water in oral insulin-fed diabetic rats

Wong TW, Sumiran N, Mokhtar MT, Kadir A

Pharm Biol, 2012 Nov;50(11):1463-6.
PMID: 22889006 DOI: 10.3109/13880209.2012.679985

In oral insulin delivery, blood glucose profiles of a subject can be a function of complicated transfer of water and insulin between gastrointestinal and blood compartments.

Matched MeSH terms: Insulin/administration & dosage
Fulltext Diabetes Care in Malaysia: Problems, New Models, and Solutions

Hussein Z, Taher SW, Gilcharan Singh HK, Chee Siew Swee W

Ann Glob Health, 2016 4 25;81(6):851-62.
PMID: 27108152 DOI: 10.1016/j.aogh.2015.12.016

BACKGROUND: Diabetes is a major public health concern in Malaysia, and the prevalence of type 2 diabetes (T2D) has escalated to 20.8% in adults above the age of 30, affecting 2.8 million individuals. The burden of managing diabetes falls on primary and tertiary health care providers operating in various settings.
OBJECTIVES: This review focuses on the current status of diabetes in Malaysia, including epidemiology, complications, lifestyle, and pharmacologic treatments, as well as the use of technologies in its management and the adoption of the World Health Organization chronic care model in primary care clinics.
METHODS: A narrative review based on local available health care data, publications, and observations from clinic experience.
FINDINGS: The prevalence of diabetes varies among the major ethnic groups in Malaysia, with Asian Indians having the highest prevalence of T2D, followed by Malays and Chinese. The increase prevalence of overweight and obesity has accompanied the rise in T2D. Multidisciplinary care is available in tertiary and primary care settings with integration of pharmacotherapy, diet, and lifestyle changes. Poor dietary adherence, high consumption of carbohydrates, and sedentary lifestyle are prevalent in patients with T2D. The latest medication options are available with increasing use of intensive insulin regimens, insulin pumps, and continuous glucose monitoring systems for managing glycemic control. A stepwise approach is proposed to expand the chronic care model into an Innovative Care for Chronic Conditions framework to facilitate implementation and realize better outcomes in primary care settings.
CONCLUSIONS: A comprehensive strategy and approach has been established by the Malaysian government to improve prevention, treatment, and control of diabetes as an urgent response to this growing chronic disease.

Matched MeSH terms: Insulin/administration & dosage
Fulltext A randomized placebo-controlled trial of alphacalcidol on the preservation of beta cell function in children with recent onset type 1 diabetes

Ataie-Jafari A, Loke SC, Rahmat AB, Larijani B, Abbasi F, Leow MK, et al.

Clin Nutr, 2013 Dec;32(6):911-7.
PMID: 23395257 DOI: 10.1016/j.clnu.2013.01.012

This participant-blinded parallel-group randomized placebo-controlled study demonstrated that alfacalcidol (vitamin D analogue) preserves beta cell function in newly diagnosed type 1 diabetes (T1DM) in children.

Matched MeSH terms: Insulin/administration & dosage
Fulltext The effects of short-term, rapid glycemic control on the peroneal nerve function and serum VCAM-1 and AGE in type 2 diabetic patients in Malaysia

Norlinah MI, Hamizah R, Md Isa SH, Wan Nazaimoon WM, Khalid BA

Indian J Med Sci, 2009 Apr;63(4):131-8.
PMID: 19414982

BACKGROUND: The role of endothelial injury and circulating adhesion molecule in the development and progression of diabetic peripheral neuropathy in the long-term has been established previously.
AIMS: To study the effects of short-term glycemic control using insulin and oral hypoglycemic agent therapy (OHA) on the peroneal nerve function and vascular cell adhesion molecule-1 (VCAM-1) and advanced glycation endproducts (AGE) levels in type 2 diabetic patients.
SETTINGS AND DESIGN: A randomized controlled study involving poorly controlled (HbA1c, 7.5%-11%) type 2 diabetic patients attending the endocrinology outpatient center in a tertiary hospital in Kuala Lumpur.
MATERIALS AND METHODS: Twenty-nine patients were randomized to receive insulin (n=15) or OHA (n=14) for 8 weeks. The glycemic variables (HbA1c, fasting plasma glucose [FPG], fructosamine), VCAM-1, serum AGE and the peroneal motor conduction velocity (PMCV) were measured at baseline and at 4-week intervals.
STATISTICAL ANALYSIS USED: Paired 't' test or Kruskal Wallis test; and the unpaired 't' test or Mann-Whitney U test were used for within-group and between-group analyses, respectively. Correlation was analyzed using Spearman's correlation coefficient.
RESULTS: Within-group analysis showed significant progressive improvement in HbA1c at weeks 4 and 8 in the insulin group. The PMCV improved significantly in both groups by week 8, and by week 4 (P = 0.01) in the insulin group. PMCV correlated negatively with VCAM-1 (P = 0.031) and AGE (P = 0.009) at week 8.
CONCLUSION: Aggressive glycemic control with insulin improves the peroneal nerve function within 4 weeks. Improvement in the serum VCAM-1 and AGE levels correlated significantly with improvement in peroneal nerve conduction velocity only in the insulin group.
Study site: Tertiary endocrinology outpatient center in Kuala Lumpur, Malaysia

Matched MeSH terms: Insulin/administration & dosage
Preparation, characterization, and in vivo evaluation of insulin-loaded PLA-PEG microspheres for controlled parenteral drug delivery

Sheshala R, Peh KK, Darwis Y

Drug Dev Ind Pharm, 2009 Nov;35(11):1364-74.
PMID: 19832637 DOI: 10.3109/03639040902939213

AIM: The aim of this study was to prepare insulin-loaded poly(lactic acid)-polyethylene glycol microspheres that could control insulin release at least for 1 week and evaluate their in vivo performance in a streptozotocin-induced diabetic rat model.
METHODS: The microspheres were prepared using a water-in-oil-in-water double emulsion solvent evaporation technique. Different formulation variables influencing the yield, particle size, entrapment efficiency, and in vitro release profiles were investigated. The pharmacokinetic study of optimized formulation was performed with single dose in comparison with multiple dose of Humulin 30/70 as a reference product in streptozotocin-induced diabetic rats.
RESULTS: The optimized formulation of insulin microspheres was nonporous, smooth-surfaced, and spherical in structure under scanning electron microscope with a mean particle size of 3.07 microm and entrapment efficiency of 42.74% of the theoretical amount incorporated. The in vitro insulin release profiles was characterized by a bimodal behavior with an initial burst release because of the insulin adsorbed on the microsphere surface, followed by slower and continuous release corresponding to the insulin entrapped in polymer matrix.
CONCLUSIONS: The optimized formulation and reference were comparable in the extent of absorption. Consequently, these microspheres can be proposed as new controlled parenteral delivery system.

Matched MeSH terms: Insulin/administration & dosage*
Comparative study of two insulin regimes in pregnancy complicated by diabetes mellitus

Nor Azlin MI, Nor NA, Sufian SS, Mustafa N, Jamil MA, Kamaruddin NA

Acta Obstet Gynecol Scand, 2007;86(4):407-8.
PMID: 17486460
Matched MeSH terms: Insulin/administration & dosage
Oral calcium pectinate-insulin nanoparticles: influences of alginate, sodium chloride and Tween 80 on their blood glucose lowering performance

Wong TW, Sumiran N

J Pharm Pharmacol, 2014 May;66(5):646-57.
PMID: 24329400 DOI: 10.1111/jphp.12192

Objective: Examine the formation of pectin-insulin nanoparticles and their blood glucose lowering properties.

Methods: The calcium pectinate nanoparticles were prepared by ionotropic gelation method, with alginate, sodium chloride or Tween 80 as additive. Their in vitro physicochemical, drug release and in vivo blood glucose lowering characteristics were evaluated.

Key findings: Spherical calcium pectinate-insulin nanoparticles were characterized by size, zeta potential, insulin content and insulin association efficiency of 348.4 ± 12.9 nm, -17.9 ± 0.8 mV, 8.4 ± 1.0% and 63.8 ± 7.4%, respectively. They released less than 25% insulin following 24 h in simulated intestinal medium and exhibited delayed blood glucose lowering effect in rats. Incorporation of solubilizer sodium chloride or Tween 80 into nanoparticles did not enhance blood glucose lowering capacity owing to sodium chloride reduced matrix insulin content and Tween 80 interacted with water and had its blood glucose dilution effect negated. Combination of nanoparticles with alginate gel to allow prolonged intestinal residence and more insulin release did not enhance their blood glucose lowering capacity because of calcium alginate-cross-linked gel formation that could retard insulin release and migration into systemic circulation.

Conclusion: Physicochemical responses of additives in vivo affected blood glucose regulation property of pectin-insulin nanoparticles.

Keywords: Tween 80; alginate; insulin; nanoparticle; pectin.

Matched MeSH terms: Insulin/administration & dosage*

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